Optimal timing of granulocyte colony-stimulating factor (G-CSF) administration after bone marrow transplantation

The positive role of G-CSF in hastening the myeloid recovery of patients undergoing allogeneic bone marrow transplantation (ALLO-BMT) or autologous bone marrow transplantation (ABMT) has recently been established. Considerable knowledge about adequate doses and route of administration has been accumulated in the past few years. Nonetheless, the optimal time to start growth-factor administration remains undetermined. We have performed a stratified study according to the source of hematopoietic progenitors (ALLO-BMT or ABMT), underlying disease and its stage, and acute graft-versus-host disease (GVHD) prophylaxis regimen and randomized patients in two arms: group A, which started G-CSF on day 0 (36 patients), and group B, which started on day +7 post-BMT (39 patients). The same dose (5 Μg/kg/day) and route of administration were employed in both groups. We found no significant differences in the time to reach an absolute neutrophil count (ANC) of 0.1, 0.5, and 1×10⁹/l and 50×10⁹ platelets/l (medians: 10 and 11, 14.5 and 14, 17 and 16, 23 and 24 days, respectively, in groups A and B). We did not find differences in the days of fever or days on antibiotic treatment with less than 1×10⁹/l ANC, rate of bacteriemia, or days of hospitalization in both groups. In contrast, a considerable saving of GCSF in B group was found (mean days of infusion in group A, 18, versus 11 in group B) (p<0.0001). This is equivalent to a saving of 1120 $US per patient. Therefore, early use of G-CSF after BMT is useless and more expensive and provides no advantage over delayed administration.     

Recombinant human granulocyte colony-stimulating factor (G-CSF) combined conditioning regimen for allogeneic bone marrow transplantation (BMT) in standard-risk myeloid leukemia

We previously suggested that using a combined conditioning regimen including rhG-CSF with allogeneic BMT in refractory AML and CML in blast crisis might reduce the rate of relapse and improve disease-free survival, without any major side effects. In this study, we used the same protocol for 10 AML patients in complete remission (CR) and 6 CML patients in the chronic phase (CP). We compared disease-free survival as well as toxic side effects of the regimen with 6 AML patients in CR and 6 CML patients in CP treated with chemoradiotherapy without G-CSF. The conditioning regimen consisted of TBI and high-dose AraC. RhG-CSF was infused continuously at a dose of 5 μg/kg/day, starting 24 hr before the initial dose of total body irradiation (TBI) until the end of AraC therapy. In all 28 cases, there were no early stage deaths due to regimen-related toxicity (RRT). None of the 10 AML cases treated with the G-CSF combined regime relapsed. In 6 AML cases treated conventionally without G-CSF, one patient died of infection and another relapsed. There were no relapses in either CML group. In the combined G-CSF group, one patient died of interstitial pneumonitis 48 days after BMT, while the rest of the CML cases are still alive. There were no relapses with rhG-CSF and no serious adverse effects in terms of RRT, acute graft vs. host disease (GVHD), or leukocyte recovery. Am. J. Hematol. 57:303–308, 1998. © 1998 Wiley-Liss, Inc.     

Granulocyte colony-stimulating factor after allogeneic bone marrow transplantation

Hematopoietic growth factors have been shown to be effective in reducing the period of neutropenia after autologous bone marrow transplantation (BMT). Initial concerns over potential aggravation of graft-versus-host disease (GVHD) and increase in the incidence of relapse in patients with myeloid leukemias influenced the number of studies using hematopoietic growth factors after allogeneic BMT. We report the experience with 50 patients treated at a single institution using granulocyte colony-stimulating factor (G-CSF) after allogeneic sibling (n = 30) and matched unrelated (n = 20) BMT. The time to an absolute neutrophil count > or = 500/microL was significantly faster in patients who received G-CSF and cyclosporine and prednisone for GVHD prophylaxis when compared with historical control patients receiving the same GVHD prophylaxis (10 v 13 days, P < .01). A similar accelerated myeloid engraftment was observed for those patients who received the addition of methotrexate for GVHD prophylaxis when compared with historical control patients receiving the same GVHD prophylaxis regimen (16 v 19 days, P < .05). The median time to engraftment for patients receiving a matched unrelated BMT and G-CSF was 17 days (range 13 to 26). We did not observe any increase in GVHD or early mortality in the matched related sibling BMT. The incidence of acute GVHD in the matched unrelated BMT recipients was also low at 21%; however, 9 patients (45%) died within 100 days of the date of BMT, similar to the experience reported with granulocyte-macrophage CSF. This study confirms the efficacy of G-CSF in accelerating myeloid engraftment after allogeneic matched sibling BMT. The higher early mortality associated with patients receiving matched unrelated BMT suggests that randomized controlled trials using G-CSF after allogeneic BMT should be performed.     

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in serum in bone marrow transplanted patients.

Colony-stimulating factors (CSF) are being increasingly used to accelerate hematopoietic recovery after bone marrow transplantation. To study the endogenous serum levels of CSF in bone marrow transplanted patients we have used immunoassays measuring granulocyte-macrophage colony-stimulating factor (GM-CSF) with a sensitivity of 0.10 ng/ml and granulocyte colony-stimulating factor (G-CSF) with a sensitivity of 0.05 ng/ml. Serum samples, taken from the conditioning treatment until engraftment, were analysed in 13 patients receiving allogeneic transplants and in eight patients receiving autologous transplants. Ten patients had acute myeloid leukemia, seven acute lymphoblastic leukemia, one acute undifferentiated leukemia, two non-Hodgkin's lymphoma and one multiple myeloma. Samples were taken 1-2 times before transplantation and 1-2 times per week after transplantation (median of 46 days in allotransplant recipients and 32 days in autotransplant recipients); 17% of the allogeneic transplanted patients and 35% of the autologous transplanted patients had detectable levels of G-CSF. In both types of transplantation the G-CSF concentrations were low: median 0.06 (range 0.05-0.14) and 0.08 (range 0.05-0.40) ng/ml respectively. GM-CSF was detected only in one analysed sample in all patients. There was no evidence of increased CSF levels related to engraftment or documented infections.     

A randomized study of erythropoietin and granulocyte colony-stimulating factor (G-CSF) versus placebo and G-CSF for patients with Hodgkin's and non-Hodgkin's lymphoma undergoing autologous bone marrow transplantation

Anemia is a universal finding in patients undergoing autologous bone marrow transplantation (BMT). Effective therapies to increase the number of autologous red blood cells could result in a lower morbidity and mortality associated with red blood cell transfusions. We examined whether the addition of erythropoietin (Epo) to intensive therapy supported by progenitor cell transplantation and granulocyte colony- stimulating factor (G-CSF) would result in a lower requirement for red blood cell transfusions. Thirty-five patients with lymphoma were randomized to receive Epo versus placebo. Epo (600 U/kg three times per week) or placebo was begun 3 weeks before administration of high-dose therapy. Epo was held during the week of the preparatory regimen, and restarted on the day after BMT. All patients also received G-CSF following BMT. No significant differences were noted between the two groups in terms of patient characteristics at pretreatment or post-BMT evaluation. There were no differences in the total number of red blood cell units transfused (median Epo: 8 v placebo: 6, P = .22) nor the number of platelet transfusions given (median Epo: 12 v placebo 5, P = .14). Engraftment of granulocytes (absolute neutrophil count > or = 500/microL) occurred in a median of 12 days (range, 9 to 33) for the patients receiving Epo and G-CSF, compared with a median of 10 days (range, 8 to 22) for those receiving placebo and G-CSF (P = .70). Likewise, there were no differences in the time to platelet count > or = 20,000/microL without further transfusions with a median of 22 days (range, 15 to 150+) for those receiving Epo and G-CSF compared with a median of 20 days (range, 11 to 54) for those patients receiving placebo and G-CSF (P = .28). The combination of G-CSF and Epo as administered in this study appears to be safe but does not result in an improvement in the total number of red blood cell transfusions or total number of single donor platelet units transfused.     

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.     

Delaying treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for hematological malignancies: a prospective randomized trial.

The use of granulocyte colony-stimulating factor (G-CSF) has been established to improve hematological recovery after allogeneic bone marrow transplantation (BMT). The optimal timing to start with G-CSF has not been determined. This study investigates whether delayed use of G-CSF starting on day 6 is as safe and efficient as starting treatment with G-CSF immediately after BMT. Thirty-eight patients undergoing allogeneic BMT were randomized to either receive post-transplant G-CSF treatment starting at day 1 or at day 6. The time to hematological recovery was monitored and the groups were compared with respect to peritransplant morbidity and mortality. Recovery of the neutrophil granulocyte counts (PMN) to >100/microl, >500/microl and >1000/microl was comparable in both groups. The nadir of the PMN counts after stopping G-CSF was also similar. There was no difference in the recovery of red blood cells and platelet counts and no difference between the two groups with respect to the number of febrile episodes, number of days with antibiotics or number of documented bacterial, fungal or viral infections. Delayed treatment with G-CSF resulted in a reduction of G-CSF treatment from 19 days to 14 days (P = 0.0017). Reducing the length of treatment by 5 days lowered G-CSF treatment costs by 26.3%. Therefore, postponing treatment with G-CSF has no influence on the hematological recovery after allogeneic BMT. There is an economical benefit of postponing G-CSF use without any clinical disadvantages.     

Comparative effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy

Two hematopoietic colony-stimulating factors, granulocyte colony- stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), have been shown to accelerate leukocyte and neutrophil recovery after high-dose chemotherapy and autologous bone marrow (BM) support. Despite their use, a prolonged period of absolute leukopenia persists during which infections and other complications of transplantation occur. We collected large numbers of peripheral blood (PB) progenitors after CSF administration using either G-CSF or GM-CSF and tested their ability to affect hematopoietic reconstitution and resource utilization in patients undergoing high-dose chemotherapy and autologous BM support. Patients with breast cancer or melanoma undergoing high-dose chemotherapy and autologous BM support were studied in sequential nonrandomized trials. After identical high-dose chemotherapy, patients received either BM alone, with no CSF; BM with either G-CSF or GM-CSF; or BM with G-CSF or GM-CSF and G-CSF or GM-CSF primed peripheral blood progenitor cells (PBPC). Hematopoietic reconstitution, as well as resource utilization, was monitored in these patients. The use of CSF- primed PBPC led to a highly significant reduction in the duration of leukopenia with a white blood cell (WBC) count under 100 and 200 cells/mL, and neutrophil count under 100 and 200 cells/mL with both GM- and G-CSF primed PB progenitor cells, compared with the use of the CSF with BM or with historical controls using BM alone. In addition, the use of CSF-primed PBPC resulted in a significant reduction in median number of antibiotics used, days in the Bone Marrow Transplant Unit, and hospital resources used. Patients receiving G-CSF primed PBPC also experienced a reduction in the median number of days in the hospital, red blood cell (RBC) transfusions, platelet transfusions, days on antibiotics, and discounted hospital charges. Phenotypic analysis of the CSF-primed PBPC indicated the presence of cells bearing antigens associated with both early and late hematopoietic progenitor cells. The use of CSF-primed PBPC can significantly improve hematopoietic recovery after high-dose chemotherapy and autologous BM support. In addition, the use of G-CSF-primed PBPC was associated with a significant reduction in hospital resource utilization, and a reduction in hospital charges.     

Clinical evaluation of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in autologous bone marrow transplantation]

We administered recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 5 micrograms/kg/day by intravenous drip infusion for 21 consecutive days in autologous bone marrow transplanted patients. The period of posttransplant neutropenia was markedly shortened by the rhG-CSF treatment; mean days required for neutrophil recovery (greater than 500/mm3) of 14.3 days in the rhG-CSF group (n = 21) versus 27.8 days in the historical control group (n = 11). More importantly, the numbers of febrile days between day 15 and day 28 were found to be fewer in the rG-CSF group than in control group. These effects were obtained without delay in the recovery of other blood cell series and without any side effect. We conclude that the posttransplant use of the rhG-CSF is beneficial for prevention and treatment of infectious complications after autologous bone marrow transplantation.     

Recombinant human granulocyte-macrophage colony-stimulating factor accelerates engraftment kinetics after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia

BACKGROUND AND OBJECTIVE: The use of recombinant human granulocyte-macrophage stimulating factor (rhGM-CSF) has been shown to be well-tolerated and to reduce post-transplantation morbidity in adults undergoing HLA-identical allogeneic bone marrow transplantation (BMT). There is however, limited experience in children. DESIGN AND METHODS: We performed a prospective, comparative multicenter trial using rhGM-CSF after allogeneic BMT in children with acute lymphoblastic leukemia (ALL). The study comprised 24 patients with ALL who received rhGM-CSF and 22 patients with ALL who did not receive rhGM-CSF. There were no statistically significant differences in the demographic characteristics between the rhGM-CSF-treated and untreated groups. rhGM-CSF was given at a dose of 10 micrograms/kg/day infusion over 4 hours from day +1 until +28 or until the absolute neutrophil count (ANC) was > or = 1 x 10(9)/L. All patients received HLA-identical sibling marrow and cyclosporine alone for graft-versus-host disease (GvHD) prophylaxis. The number of cells infused was similar in both groups. A software program (Statview 4.0, Abacus Concept, Inc., Berkeley, CA, USA) was used for statistical analysis. RESULTS: The median of days to achieve ANC > or = 0.5 x 10(9)/L was shorter in the rhGM-CSF-treated patients (14 days vs 18.5 days; p < 0.0001). Patients who received rhGM-CSF had a lower incidence of grade III-IV mucositis. The duration of hospital stay was significantly shorter in patients who received rhGM-CSF (31 days vs 45 days; p < 0.005). No differences in GvHD severity, relapse or survival were observed. At the dose and schedule used in the present study, rhGM-CSF was well-tolerated and no side effects were observed. INTERPRETATIONS AND CONCLUSIONS: rhGM-CSF at a dose of 10 micrograms/kg/day in children with ALL undergoing allogeneic BMT is well tolerated, accelerates neutrophil and platelet engraftment, reduces the intensity and severity of mucositis and permits a more rapid discharge from hospital.     

Characteristics of engraftment after repeated autologous bone marrow transplantation

The rate of engraftment after autologous bone marrow transplantation (ABMT) is extremely variable and largely unpredictable. To identify factors influencing engraftment, we studied 35 patients with refractory germ cell tumors undergoing high-dose chemotherapy with carboplatin (900-2000 mg/m2) and etoposide (1200 mg/m2) with bone marrow rescue. Prior to the initiation of chemotherapy, bone marrow sufficient for two marrow infusions was harvested (range 0.86-4.82 x 10(8) nucleated cells per kg). All 35 patients received half of the collected bone marrow 3 days after the last dose of chemotherapy; 23 responders received a second round of the same chemotherapy followed by infusion of the second half of the bone marrow. Eighteen patients could be compared for the two transplant episodes. The "rate of engraftment" was defined as the unweighted mean of four parameters: 1) the number of days until the absolute granulocyte count surpassed 0.2 x 10(9)/liter, 2) the number of days until the absolute granulocyte count surpassed 0.5 x 10(9)/liter, 3) the number of days until the last platelet transfusion, and 4) the number of days until the reticulocyte count surpassed 25 x 10(9)/liter. No significant correlation was found between rate of engraftment and such factors as the number of nucleated cells per kg infused, the dose of chemotherapy, extent of prior chemotherapy, tumor response to the high-dose chemotherapy, age of the patient, or the days of granulocytopenic fever (all p greater than 0.20). In contrast, a close correlation was found for the number of units of platelets (p = 0.005) and red blood cells (p = 0.006) transfused following each of the two transplants. There was no significant difference between rate of engraftment after first and second transplantation. Comparison of these data with the results obtained in reported ABMT with separate harvests suggests that the characteristics of the infused marrow determine the rate of engraftment after ABMT. This model of repeated transplantation could provide an important tool for assessing the therapeutic efficacy of hematopoietic growth factors.     

Systemic capillary leak syndrome after granulocyte colony-stimulating factor (G-CSF)

Capillary leak syndrome (CLS) commonly occurs in the intensive care setting. CLS is seen in conditions such as septic shock or may result from conditions such as multitrauma and pancreatitis, which result in the systemic inflammatory response syndrome (SIRS). We present two cases in which both patients suffered with CLS, which we believe was caused following administration of granulocyte colony-stimulating factor, to our knowledge not described in the intensive care patient previously. We discuss how these patients management differs from other intensive care unit patients with CLS and how it is important to diagnose this condition early in haematological oncology cases.     

Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation

Cytomegalovirus (CMV) infection was detected in 65 of 143 (45%) autologous bone marrow transplant (BMT) patients. CMV pneumonitis occurred in only 2% of the patients and CMV retinitis occurred in none. Infection occurred in half of the 40 initially seronegative patients and 47% of the 94 initially seropositive patients. Among initially seropositive patients, platelet recovery was slower in infected patients than in those not infected (97 v 35 days median, P = .003), and neutrophil recovery was slightly delayed in infected patients (31 days v 24 days, P = .02). Although the incidence of CMV infection was comparable in autologous and allogeneic BMT patients, CMV pneumonitis was less frequent in autologous BMT patients (2% v 12%, P less than .001). The risk for CMV pneumonitis in autologous BMT patients was comparable with that in allogeneic BMT patients without graft-v-host disease (GVHD) (2% v 6%), but significantly lower than the risk in allogeneic BMT patients with GVHD (2% v 23%, P less than .001).     

Histological alterations in bone marrow in patients with late engraftment after autologous bone marrow transplantation

Bone marrow histology after bone marrow transplantation has rarely been studied. Here, we reviewed the pre- and post-transplant bone marrow biopsies (BMB) of 40 acute myelogenous leukemia (AML) patients autografted in our center, 28 with normal and 12 with delayed peripheral recovery. The two groups were comparable in terms of previous therapy, disease phase and the number of infused cells, and received the same conditioning regimen. In the former group, reduced bone marrow cellularity and mild reticulin abnormalities were usual histological findings; in the latter, five patients had the same pattern, but the other seven had an almost undetectable hematopoietic parenchyma and severe reticulin derangement. One of these seven patients died of reactivated hepatitis B virus infection; the others eventually achieved peripheral recovery, with none of them experiencing a relapse. Autografted AML patients are excellent subjects for histological investigations. They account for the majority of delayed engraftments, the contribution of extramedullary components to the timing of engraftment is minimal, and leukemia relapse cannot be ruled out. These results suggest that BMB is a useful investigation in the work-up of late engraftment. A high degree of reticulin derangement with an almost undetectable hematopoietic parenchyma appear to be the morphological hallmarks of late engraftment.     

GM-CSF therapy for delayed engraftment after autologous bone marrow transplantation

Based on previous observations that granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes granulocyte recovery following chemotherapy, we evaluated the effect of recombinant human GM-CSF on hematopoietic progenitors and clinical outcome in six patients with delayed engraftment (greater than 55 days) after high-dose therapy and autologous bone marrow transplantation (ABMT). Three patients responded to a 14-day course of GM-CSF (10 micrograms/kg body weight/day) with at least a sevenfold rise in circulating granulocytes and a corresponding increase in granulopoietic activity in the bone marrow. A fourth patient died of infection on the 8th day of GM-CSF therapy with no evidence of response, and the remaining two, one of whom received a lower dose of GM-CSF (5 micrograms/kg/day), did not respond. There was no change in platelet or red cell transfusion requirements in any patient during the treatment. In two of the three responders, the granulocyte counts returned to pretreatment levels by 4 and 7 weeks after stopping the drug, respectively. We observed a marked increase in marrow-derived as well as in circulating granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) by the end of the 14-day course of GM-CSF in the three responders. There was no change in the frequency of circulating or marrow-derived erythroid (erythroid burst-forming units, BFU-E) or multilineage (multilineage colony-forming units, CFU-GEMM) progenitors. The results indicate that GM-CSF therapy in patients with markedly delayed engraftment after ABMT may stimulate granulopoiesis, but the effect is transient in some patients.     

Circulating erythropoietin levels after bone marrow transplantation: inappropriate response to anemia in allogeneic transplants.

We studied 24 recipients of autologous bone marrow transplantation (ABMT) or allogeneic BMT (BMT) to determine whether impaired erythropoietin (Epo) response to anemia could delay full erythropoietic recovery. Observed Epo levels were compared with predicted levels based on the relationship between Epo and hematocrit in 125 control subjects. Circulating Epo levels were normal during conditioning and the early posttransplant period. Between days 21 and 180, Epo levels remained normal in ABMT patients but were inappropriately low for the degree of anemia in BMT patients. Median time to full erythropoietic engraftment was longer in BMT than in ABMT recipients. Circulating Epo returned to appropriate levels after day 180, except in patients with active cytomegalovirus infection. We conclude that impaired Epo response to anemia can contribute to delayed erythropoietic recovery after allogenic BMT. Renal toxicity of ciclosporin, interaction between host and donor marrow, and cytomegalovirus infection might play a role. This study could support the use of recombinant human Epo to accelerate erythropoietic engraftment after BMT.     

Effect of exogenous recombinant human granulocyte and granulocyte-macrophage colony-stimulating factor on neutrophil function following allogeneic bone marrow transplantation.

Functional activity of peripheral blood granulocytes was assessed in seven patients and in their normal donors following allogeneic bone marrow transplantation (BMT). Functions studied included superoxide generation (O2-), intracellular killing of Staphylococcus aureus, phagocytosis, and killing of Candida albicans. Neutrophils were tested following preincubation with 300 pM granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.2 nM granulocyte colony-stimulating factor (G-CSF), or buffered solution (diluent) as control. Our data indicate that following BMT, both recipients and their normal donors show GM-CSF- and G-CSF-induced increases in: 1) O2- production in response to fMet-Leu-Phe (fMLP), 2) killing of S. aureus, and 3) phagocytosis of C. albicans. In two patients that showed low candidacidal activity, GM-CSF and G-CSF markedly enhanced the cytotoxic activity of the cells. Our studies indicate that GM-CSF and G-CSF increase "oxygen-dependent" oxidative activities in neutrophils from BMT recipients and their normal donors and enhance the antimicrobial activity of the cells.