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Keywords:

  • colony stimulating factor;
  • BCSH;
  • G-CSF;
  • guideline;
  • haematological;
  • malignancy

Haematological malignancies are associated with a high rate of infectious morbidity and mortality due to neutropenia, particularly in elderly patients, either as a direct result of the disease itself or as a result of the intensive chemotherapy regimens now used to combat these diseases. In fact, neutropenia and infection are the major dose-limiting side-effects of chemotherapy. The incidence of febrile neutropenia (FN) depends on a number of factors, including the dose intensity of the chemotherapy, the prior history of the patient and the presence or absence of any co-morbid conditions. In the past decade, there have been many clinical trials investigating the potential benefits of adjunctive therapy with colony-stimulating factors (CSFs), both to ameliorate or prevent profound neutropenia and its potentially life-threatening consequences, and to enhance the outcome of peripheral blood progenitor cell (PBPC) grafting and bone marrow transplantation (BMT). The specific aims of such therapy have been:

  • •  
    to prevent neutropenia-associated infection, with a view to reducing morbidity, improving patient quality of life, decreasing antibiotic usage and duration of hospitalization, and increasing cost-effectiveness of treatment;
  • •  
    to avoid the necessity for chemotherapy dose reduction and/or delay due to neutropenia (i.e. to achieve ‘planned dose on time’);
  • •  
    to enhance outcome after consolidation chemotherapy in patients achieving complete remission on induction chemotherapy;
  • •  
    to ‘prime’ certain types of malignant cells such that they are more sensitive to some cytotoxic agents;
  • •  
    to mobilize PBPCs before collection;
  • •  
    to stimulate stem cell proliferation after PBPC infusion or BMT.

Based on the minimal comparative data available and the results of clinical trials, there is no evidence of any difference between the available CSFs [granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF)] in terms of efficacy or outcome providing the growth factors are given at the recommended dose (Ozer et al, 2000). These guidelines therefore do not differentiate between the two types of agent, although specific agents may be referred to in the context of clinical trial results.

The following guidelines present recommendations for primary versus secondary prophylaxis with CSFs, and specific evidence and recommendations for the use of CSFs in the various haematological malignancies and transplant procedures, including those from the most recent update of the American Society of Clinical Oncology (ASCO) guidelines, which are summarized in Appendix 1 (Ozer et al, 2000).

Methods

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

A systematic review of the literature was undertaken from 1986 up to March 2002. The following diseases and transplant procedures were assessed:

Acute myeloid leukaemia (AML)

Acute lymphoblastic leukaemia (ALL)

Myelodysplastic syndromes (MDS)

Aplastic anaemia (AA)

Non-Hodgkin's lymphoma (NHL)

Hodgkin's disease (HD)

Lymphoblastic lymphoma (LL)

PBPC mobilization and transplantation.

Studies were identified by searching the following databases:

Medline

EMbase

Cancerlit

Cochrane (UK) – Database of systematic reviews (CDSR)

  • – The Cochrane Controlled Trials Register (CCTR)

  • – Database of Abstract of Review of Effectiveness (DARE).

Medline, EMbase and Cancerlit were searched to identify any randomized controlled trials (RCTs) using a modified version of the Cochrane Collaboration search strategy (Dickerson, 1996). We used only part of the complex Cochrane strategy using the OVID search strategy of RCT, controlled clinical trial, RCTs, random allocation, double-blind method, single-blind method, clinical trial, comparative study as search lines. Authors of trials were not contacted for further information. More general search strategies were used to identify non-randomized comparator studies and, where required, case histories. Meeting abstracts were hand searched to ensure no information was missed. We used previous papers to identify references that were not otherwise found.

Studies were classified as follows:

  • •  
    prospective RCTs
  • •  
    prospective cohort studies with a non-randomized comparator (including historical controls)
  • •  
    retrospective cohort studies with non-randomized comparators
  • •  
    case histories.

For each disease or transplant procedure, a decision was made as to which level of evidence should be considered based on the number of trials and patients. If sufficient evidence was available from RCTs, then no other evidence was reviewed. Otherwise, all the other categories were included in the search.

Full papers relating to the highest levels of evidence in each disease or transplant procedure were ordered and reviewed by at least one clinical reviewer. Search strategies identified over 1500 citations. From the titles and abstracts of these papers, the systematic review process identified 299 publications as potentially relevant (98 lymphoma, 117 leukaemia, 36 PBPC transplantation, 24 PBPC mobilization and 24 post-PBPC and BMT). When studies generated multiple publications the most recent publications containing sufficient information were used. Quantitative analysis of the publications was not performed.

The evidence for each of the guideline categories was assessed by the authors who represent specialists in the broad field of haematology and haemato-oncology and transplantation, within teaching hospitals and district hospitals. Draft guidelines were written based on the level of evidence supporting each statement (Appendix 2). The draft guidelines were reviewed by the haemato-oncology task force of the British Committee for Standards in Haematology, and then distributed for peer review to 60 UK haematologists. The final version was then ratified by the haemato-oncology task force and the British Society for Haematology Committee. The group disseminates its guidelines freely through its website at http://www.bcshguidelines.org.

Primary prophylaxis

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

At present, the routine use of CSFs as primary prophylaxis in previously untreated patients undergoing induction chemotherapy is not recommended, as the proportion of patients who might benefit is small compared with the cost and inconvenience of CSF administration (Ozer et al, 2000). Moreover, it is possible that CSFs themselves may induce fever that may be interpreted as FN, leading to the inappropriate use of empirical antibiotics. However, primary CSF treatment may be warranted in high-risk patient populations where the incidence of FN is at least 40%, e.g. patients with acquired immunodeficiency syndrome (AIDS)-related NHL, dose-escalated schedules for lymphoma, leukaemia, elderly patients, as well as those with pre-existing neutropenia, poor performance status, advanced cancer, decreased immune function or already-active tissue infections. In these cases, there is evidence that CSFs may reduce the need for hospitalization and antibiotic therapy, with associated therapeutic savings, although no clinical outcome benefit has yet been demonstrated in terms of response rates and disease-free or overall survival (Ozer et al, 2000).

Secondary prophylaxis

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

This term is used to define use of CSFs in a patient who has already experienced an episode of FN, either to prevent further infection or to allow delivery of subsequent chemotherapy on schedule. Use of a CSF in this situation would appear to be logical, but there is no published evidence to demonstrate improved overall survival when secondary prophylaxis is given. However, given that the alternative strategy is dose reduction/dose delay and that there is emerging evidence of improved survival in some tumours with CSF-facilitated dose intensification (see NHL section), it may be reasonable to extrapolate this evidence to support the use of CSFs to maintain the planned delivery of full-dose chemotherapy (Lepage et al, 1993).

Adjunctive use of CSFs

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

It is necessary to distinguish between afebrile and febrile neutropenic patients. One randomized trial showed no clinical benefit for the routine use of CSFs in afebrile neutropenic patients (Hartmann et al, 1997). In febrile patients, the results of nine randomized trials in patients with solid tumours or haematological malignancies (Biesma et al, 1990; Maher et al, 1994; Riikonen et al, 1994; Mayordomo et al, 1995; Anaissie et al, 1996; Vellenga et al, 1996; Mitchell et al, 1997; Ravaud et al, 1998; Garcia-Carbonero et al, 2001) showed a consistent reduction in the duration of neutropenia [absolute neutrophil count (ANC) < 0·5 × 109/l] but varied in terms of clinical outcome (e.g. antibiotic usage and hospitalization) and cost-effectiveness. This suggests that CSFs should not be used routinely as adjunctive therapy to antibiotics in patients with uncomplicated FN. However, the ASCO guidelines (Ozer et al, 2000) suggest that use of CSFs should be considered in patients at high risk of infection-associated complications and adverse prognostic factors, such as those with:

  • •  
    profound neutropenia (ANC < 0·1 × 109/l)
  • •  
    pneumonia
  • •  
    hypotension
  • •  
    multiorgan dysfunction (sepsis syndrome)
  • •  
    invasive fungal infection
  • •  
    elderly patients or those with post-treatment lymphopenia.

Recommendations

  • •  
    Primary prophylaxis is not routinely recommended unless the expected incidence of febrile neutropenia is greater than 40% (level IIa, grade B).
  • •  
    Secondary prophylaxis cannot be routinely justified because of a lack of available evidence but is indicated for tumours in which dose reduction/dose delay would compromise overall survival (level III, grade B).
  • •  
    Adjunctive treatment is not recommended for patients with uncomplicated febrile neutropenia (level Ib, grade A) but should be considered in patients with the poor prognostic factors listed in the text (level IV, grade C).

Use Of Csfs In Association With Chemotherapy

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

Many studies have now been conducted to investigate the potential benefits of CSFs for the maintenance of chemotherapy dose intensity and management of infectious complications associated with chemotherapy-induced neutropenia in patients with leukaemia, MDS (AA), NHL and HD. As far as possible, the following data and recommendations are drawn from randomized clinical trials. In most studies, the CSFs were administered at least 1 d after completion of chemotherapy in order to minimize any theoretical risk of stimulating leukaemic cell growth, although ‘priming’ of malignant cells to enhance sensitivity to chemotherapy has been investigated in AML.

Induction/post induction.  Randomized trials of CSF administration after induction chemotherapy in AML all demonstrated a consistent reduction (by ≈ 2–6 d) in time to neutrophil recovery to ≥ 0·5 × 109/l. (Dombret et al, 1995; Rowe et al, 1995; Stone et al, 1995; Takeshita et al, 1995; Zittoun et al, 1996; Heil et al, 1997; Lowenberg et al, 1997a,b; Godwin et al, 1998; Witz et al, 1998; Usuki et al, 2002). Most also showed a significant reduction in the duration of hospital stay and antibiotic usage. Three trials demonstrated evidence of an increase in either clinical response rate (Dombret et al, 1995) or patient survival [overall (Rowe et al, 1995) or disease-free (Witz et al, 1998)]. Importantly, there was no evidence of any stimulation of leukaemic cell growth or drug resistance in any of these studies. In each study, CSF was given either 1 d after completion of induction chemotherapy or 2–3 d later based on evidence of marrow aplasia on biopsy. However, the results in terms of duration of neutropenia were similar in all studies, suggesting that there is no need for routine bone marrow biopsies before starting CSF (Schiffer, 1996; Ozer et al, 2000).

As elderly AML patients (≥ 60 years of age) appear to be more at risk of death from neutropenic infections than younger patients, the elderly may be better candidates for CSF therapy (Schiffer, 1996). The ASCO authors recommended that CSF treatment after induction therapy in AML should be given if it can be shown that the cost of the growth factor is balanced against any shortening of hospitalization. An economic analysis of data from seven institutions participating in the Eastern Cooperative Group (ECOG) phase III (Rowe et al, 1995) study showed that treatment with GM-CSF after chemotherapy was associated with overall savings of US$2310 compared with placebo, but further cost-effectiveness data are needed before definitive conclusions can be drawn.

Post-consolidation therapy.  Two trials, in which G-CSF was given after consolidation chemotherapy in AML patients in complete remission, showed a marked decrease in the duration of neutropenia compared with placebo, as well as a reduction in the use of antibiotic therapy (Heil et al, 1997; Harousseau et al, 2000).

Priming of leukaemia cells.  So far, all except one of the trials that have investigated whether concomitant treatment with CSFs could be used to prime leukaemia cells to enhance their sensitivity to S-phase-specific agents have shown no evidence of any increase in the rate or duration of response or increase in overall survival, whether in previously treated or untreated patients (Ohno et al, 1994; Hansen et al, 1995; Zittoun et al, 1996; Lowenberg et al, 1997a,b; Uyl-de Groot et al, 1998; Witz et al, 1998; Thomas et al, 1999). One complex study in poor-prognosis newly diagnosed AML did find that the addition of G-CSF ± all-trans retinoic acid (ATRA) to chemotherapy improved the complete remission rate compared with either chemotherapy alone or chemotherapy plus ATRA, but there was no subsequent impact on survival (Estey et al, 1999). The timing of CSF administration, that is whether started a day or two before chemotherapy (Ohno et al, 1994; Hansen et al, 1995; Zittoun et al, 1996; Lowenberg et al, 1997b; Uyl-de Groot et al, 1998), at the same time as chemotherapy (Zittoun et al, 1996; Lowenberg et al, 1997a; Witz et al, 1998; Estey et al, 1999) or between courses of chemotherapy (Thomas et al, 1999), did not appear to influence outcome. There was no apparent adverse effect on leukaemia cell growth, but one study did find an unexpected level of hepatotoxicity with GM-CSF in the form of hypoalbuminaemia and a reduction in coagulation factors (which could be prevented by administering vitamin K) (Hansen et al, 1995). One study that analysed the costs associated with treatment found that these were significantly higher (by around US$6000) when a CSF (GM-CSF in this case) was used (Uyl-de Groot et al, 1998). Another economic evaluation has been carried out by US investigators (Freund & Dittus, 1995). This use of CSFs should only be considered in the setting of clinical trials.

Acute lymphoblastic leukaemia

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

In six prospective, randomized trials in adults and children with ALL, CSFs (G-CSF in all cases) given during (Ottmann et al, 1995; Geissler et al, 1997; Larson et al, 1998), after (Pui et al, 1997) or between courses (Welte et al, 1996; Clarke et al, 1999) of chemotherapy has been shown to shorten the duration of neutropenia by up to 8 d when given to patients receiving induction and post-remission chemotherapy. As in AML, the effects on clinical parameters varied between the studies. The largest adult study showed a higher complete response rate in the G-CSF-treated group (P = 0·04) (Larson et al, 1998), but no trial showed any difference in terms of disease-free or overall survival. In five studies, there was evidence of a benefit with G-CSF in terms of fewer documented infections, shorter in-hospital stays and/or reduced antibiotic usage (Welte et al, 1996; Geissler et al, 1997; Pui et al, 1997; Larson et al, 1998; Clarke et al, 1999). Four studies also reported that treatment with G-CSF was associated with better adherence to or intensification of chemotherapy schedules (Ottmann et al, 1995; Welte et al, 1996; Clarke et al, 1999; Michel et al, 2000). The ASCO authors considered the data in ALL ‘sufficient to recommend G-CSF administration begun after completion of the first few days of chemotherapy of the initial induction or first postremission course, thus shortening the duration of neutropenia of less than 1000/mm3 by approximately 1 week’.

Myelodysplastic syndromes

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

Randomized dose-finding studies with GM-CSF alone for 8 weeks in neutropenic MDS indicated that such treatment could increase both neutrophil and eosinophil counts and was generally well tolerated (Willemze et al, 1992; Yoshida et al, 1995). Three studies carried out since then in the US, Italy and The Netherlands, in which MDS patients were randomized to receive chemotherapy with or without G-CSF during (Estey et al, 1999; Ossenkoppele et al, 1999) or after chemotherapy (Bernasconi et al, 1998), all showed a significant benefit for G-CSF (5 µg/kg/d or 200 µg/m2/d) in terms of shortening of neutropenia (Bernasconi et al, 1998; Estey et al, 1999; Ossenkoppele et al, 1999). All three studies also provided at least some evidence of an improved response rate with G-CSF, although none showed any influence on duration of response or survival. However, in the Italian trial, in which G-CSF was given after chemotherapy, the higher remission rate and lower incidence of infection meant that the number of allo-transplantable cases was increased significantly compared with the group not receiving G-CSF (Bernasconi et al, 1998). The Dutch investigators also reported a reduction in the interval between induction and consolidation chemotherapy in patients on G-CSF as a result of the shortened duration of neutropenia (Ossenkoppele et al, 1999). None of the studies reported an increased rate of transformation to overt AML with CSF treatment, although this is a theoretical risk (Shinohara, 2000). Two studies have also suggested that the addition of erythropoietin to G- or GM-CSF in MDS patients with anaemia may improve haemoglobin response rates (Hellstrom-Lindberg et al, 1998; Thompson et al, 2000), with a potentially synergistic effect (Hellstrom-Lindberg et al, 1998).

The above results all suggest that CSFs (possibly with erythropoietin in anaemic patients) may be beneficial in MDS, at least for the resolution of neutropenia and possibly to shorten the interval between courses of chemotherapy. Intermittent use of CSFs is also beneficial in patients with severe neutropenia and recurrent infection (Ozer et al, 2000). However, prolonged or continuous treatment with CSFs in MDS should be approached cautiously.

Acquired aplastic anaemia and inherited bone marrow failure

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

So far, there are limited trial data on the use of CSFs in patients with acquired AA. A review paper published in 1998 considered the available evidence from non-randomized studies and case reports (Kumar & Alter, 1998). This indicated that neutrophil responses to G-CSF and GM-CSF in acquired AA were ‘not uncommon’, particularly in those with non-severe AA. Studies are ongoing with a variety of other haematopoietic growth factors in acquired AA, including erythropoietin, stem cell factor, Flt3 ligand and thrombopoietin, but there are no definitive data so far. Treatment with interleukin (IL)-3 has been shown to benefit some patients, but is associated with severe systemic side-effects and is no longer available for clinical use.

Data from the few randomized studies indicate that the addition of G-CSF to immunosuppressive therapy has no benefit for the prophylaxis of infections in AA, but may be useful in patients with complicated bacterial or fungal infections (Kojima, 1999; Kojima et al, 2000). However, as there is a theoretical risk that CSFs may add to the risk of transformation to MDS or AML, it has also been recommended that they should not be used as sole therapy and that their use in combination with immunosuppressive therapy should currently be restricted to randomized trials (Marsh, 2000).

The use of growth factors in inherited bone marrow failure syndromes has also been reviewed (Kumar & Alter, 1998). The authors reported that G-CSF is the most effective agent identified so far, with good neutrophil responses in a range of disorders, including Kostmann's syndrome, Schwachman–Diamond syndrome, Fanconi anaemia, dyskeratosis congenita and Pearson's syndrome.

Non-Hodgkin's lymphomas.  There have been seven randomized controlled trials in which GM- or G-CSF was used as primary prophylaxis in patients with high-grade NHL undergoing induction chemotherapy (Pettengell et al, 1992; Gerhartz et al, 1993; Aviles et al, 1994; Fridrik et al, 1997; Gisselbrecht et al, 1997; Zinzani et al, 1997; Bjorkholm et al, 1999). Although none of these studies showed any clear benefit in terms of tumour response or survival, meta-analysis of the data provided strong evidence of other clinical benefits for the CSFs compared with controls, including a 44% reduction in the incidence of neutropenia, a 43% reduction in the risk of severe or clinically relevant infection, an 80% reduction in the risk of chemotherapy delays and a 47% reduction in duration of hospital stay, all of which were statistically significant (Sweetenham et al, 2000; Bohlius et al, 2001).

G-CSF has also been used to facilitate reduction in the interval between CHOP (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone) chemotherapy from the current standard of 3 weeks to 2 weeks. In the German High Grade NHL Study Group trial of this approach in patients over 60 years of age, the overall survival increased from 49% to 64·3% (at a median observation time of 40 months) with 2-weekly CHOP (plus G-CSF from d 4 to neutrophil recovery) compared with the 3-weekly regimen without G-CSF (Pfreundschuh et al, 2001).

Hodgkin's disease.  One randomized study has been carried out in the UK in which 45 patients receiving either MOPP (methotrexate, oncovin, procarbazine, prednisone) or MOPP/EVAP (etoposide, vinblastine, doxorubicin, prednisone) chemotherapy for Hodgkin's disease were randomized to receive either adjunctive G-CSF (on days when chemotherapy was not administered) or no G-CSF (Dunlop et al, 1998). In the MOPP arm, G-CSF resulted in significant reductions in the median duration of leucopenia and in the severity of white blood cell nadir, but had no effect on platelets or haemoglobin. In contrast, in the group receiving MOPP/EVAP, G-CSF treatment was associated with significant reductions in median nadirs of both haemoglobin and platelets, but had no effect on duration or depth of leucopenia. G-CSF had no statistically significant influence on chemotherapy dose intensity with either MOPP or MOPP/EVAP, nor was there any evidence in either chemotherapy group of any influence of G-CSF on the incidence of FN, infections or hospital stay.

In a small, non-randomized trial in which 16 G-CSF-treated patients with HD were compared with 25 matched historical controls, the use of G-CSF was associated with significantly higher dose intensity during MOPP/ABVD therapy, but there was no difference in terms of complete response to chemotherapy or survival (Gustavsson, 1997).

T-cell leukaemia and lymphoblastic lymphoma.  One open-label randomized trial of G-CSF in intensive induction and continuation chemotherapy for T-cell leukaemia (T-ALL) and advanced-stage lymphoblastic lymphoma (ASLL) of childhood has been carried out (Laver et al, 1998). In this study, 56 patients with T-ALL and 33 with ASLL were randomized to receive G-CSF or not after induction therapy and after two continuation therapy cycles. There were no apparent effects of G-CSF in the induction phase, but the duration of neutropenia in the continuation therapy phase was significantly shorter in the G-CSF arm. There were no significant differences in terms of hospitalization or delays in chemotherapy.

Recommendations

  • •  
    AML. The routine use of CSF is recommended after consolidation chemotherapy (level Ib, Grade A). CSF is recommended after induction if it is appropriate to reduce hospital stay or antibiotic usage.
  • •  
    ALL. G-CSF is indicated to reduce the severity of neutropenia following intensive phases of therapy (level Ib, grade A).
  • •  
    MDS. CSFs are indicted to reduce the severity of neutropenia in patients receiving intensive chemotherapy (level Ib, grade A). CSFs are also recommended on an intermittent basis for patients with neutropenia and infection (level IV, grade C), but continuous prophylactic use is not routinely justified.
  • •  
    Aplastic anaemia. There is insufficient evidence to make any general recommendations and hence patients should be given CSFs only on an individual therapeutic trial basis (level IV, grade C).
  • •  
    Bone marrow failure syndromes. G-CSF is recommended when improvement of neutrophil count is appropriate (level III, grade B).
  • •  
    Malignant lymphomas. There is evidence to support the routine use of CSFs to reduce the incidence of infection, chemotherapy delay and hospitalization especially when the risk of febrile neutropenia exceeds 40% (level Ia, grade A). There is also emerging evidence of improved survival with G-CSF-supported dose intensification in elderly patients with high-grade NHL (level Ib, grade A). At present, this evidence is insufficient to justify a change in policy in all patients with lymphoma, but elderly patients may benefit from G-CSF support.

Csfs for pbpc mobilization

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

The rationale for CSF treatment before PBPC collection in lymphoma patients is the mobilization of PBPCs into the circulation, thereby increasing the number of progenitor cells acquired. This could reduce the frequency, duration and cost of leukapheresis procedures, and potentially increase the speed of haematological recovery after transplantation (Ozer et al, 2000).

Mobilized versus non-mobilized PBPC

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

A number of non-randomized studies have demonstrated the effectiveness of GM- or G-CSF for autologous PBPC mobilization compared with non-mobilized controls in terms of more rapid neutrophil recovery after transplantation, with reduced platelet and red blood cell transfusion requirements and shorter hospital stay (Chao et al, 1993; Bishop et al, 1994; Lamy et al, 1994; Nademanee et al, 1994). There is also some evidence of cost benefits with mobilization (Chao et al, 1993).

In a randomized study in which the efficacy of G-CSF and GM-CSF was compared for autologous PBPC mobilization in HD patients, there was no apparent difference between the agents in terms of median cell yield or time to haematological recovery after transplant (Hohaus et al, 1998). Other authors have suggested that a combination of GM- and G-CSF might optimize PBPC mobilization (Ho et al, 1996).

Two studies in which the combination of cyclophosphamide plus G-CSF was compared with G-CSF alone reported that the combination might mobilize CD34+ cells that are functionally different (Cesana et al, 1998), and that it may be more cost-effective compared with G-CSF alone (Meisenberg et al, 1998). In a non-randomized study, treatment with G-CSF alone did not give as high a yield of CD34+ cells compared with chemotherapy plus GM-CSF, but the yield with G-CSF was considered adequate in most patients, with less toxicity and simplified procedures compared with the combination treatment (Alegre et al, 1997). Chemotherapy plus G-CSF has also been used successfully to mobilize Philadelphia-negative PBPCs in more than a quarter of CML patients ineligible for allografting (Carella et al, 1998).

The dose of CSF used has varied between the studies, but there is some evidence that higher doses of G-CSF (10 µg/kg/d versus 5–6 µg/kg/d) (Dreger et al, 1994; Nademanee et al, 1994) or twice-daily G-CSF (6 or 8 µg/kg/12 h versus 10 µg/kg/d) (Arbona et al, 1998) may yield a greater content of CD34+ cells.

Mobilized PBPC versus BMT

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

Four randomized trials have shown benefits for the use of mobilized PBPC transplantation (autologous or allogeneic) compared with BMT (Schmitz et al, 1996, 1998; Blaise et al, 2000; Bensinger et al, 2001). In a study in which 58 lymphoma patients were randomized to receive autologous G-CSF-mobilized PBPC or autologous BMT, the PBPC strategy was associated with significant reductions in the number of platelet transfusions, time to platelet and neutrophil recovery and time to discharge from hospital (Schmitz et al, 1996). One randomized study of 66 patients, comparing G-CSF-mobilized allogeneic PBPC transplantation with allogeneic BMT [from human leucocyte antigen (HLA)-identical relatives in each case], showed no differences in terms of haematopoietic recovery, mortality or survival, but the PBPC donors spent fewer nights in hospital and had fewer days with restricted activity compared with the marrow donors (Schmitz et al, 1998). Two more recent randomized studies did show significant benefits for G-CSF-mobilized PBPC compared with BMT in terms of neutrophil and platelet recovery (Blaise et al, 2000; Bensinger et al, 2001). One of these also reported a trend for improved overall survival (66% versus 54%, P = 0·06) and a significance increase in disease-free survival (65% versus 45%, P = 0·03) at 2 years for the PBPC recipients compared with marrow recipients respectively (Bensinger et al, 2001). The other reported that the shorter length of hospitalization associated with G-CSF-mobilized PBPC transplant resulted in a decrease in the total cost of the procedure during the first 6 months (Blaise et al, 2000).

A number of non-randomized studies have also provided evidence of the benefits and tolerability of donor PBPC mobilization compared with allogeneic BMT (Faucher et al, 1994; Bensinger et al, 1995; Korbling et al, 1995; Schmitz et al, 1995a; Pavletic et al, 1997). In one of these studies, total costs in the G-CSF-mobilized PBPC group were lower than those with BMT (with or without G-CSF) (Faucher et al, 1994).

Graft-versus-host disease

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

In the case of donor PBPC mobilization, there is a theoretically increased risk of graft-versus-host disease (GVHD) compared with unmodified marrow grafts, as PBPCs contain at least 1 log more T cells (Storek et al, 1997). With the exception of two studies (Storek et al, 1997; Blaise et al, 2000), however, the risk of GVHD did not appear to be increased with the use of CSFs in the studies described above (Faucher et al, 1994; Bensinger et al, 1995, 2001; Korbling et al, 1995; Schmitz et al, 1995a; Pavletic et al, 1997; Schmitz et al, 1998), although this is currently under further investigation.

Recommendation

CSFs are indicated for the mobilization of PBPCs.

Autologous PBPC transplantation

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

Most randomized trials using CSFs after high-dose chemotherapy and autologous PBPC transplantation have shown them to be valuable in terms of significantly shortening the duration of neutropenia and hospitalization (Nademanee et al, 1994; Klumpp et al, 1995; Linch et al, 1997; Lee et al, 1998a) and possibly reducing costs (Schmitz et al, 1996; Lee et al, 1998a; Tarella et al, 1998). In a UK study, for example, the clinical benefits of G-CSF started at d +5 after autologous PBPC transplant were shown to be associated with a mean cost saving of £1816 per patient, even taking into account the cost of the G-CSF (Lee et al, 1998a). One placebo-controlled trial showed no benefit for therapy with GM-CSF after transplantation of GM-CSF-mobilized PBPCs, with significantly fewer febrile days on placebo (Legros et al, 1997).

The optimal timing of CSF administration after autologous PBPC transplantation is still under investigation. Two randomized studies demonstrated no significant differences in efficacy between early or delayed G-CSF [d +1 versus d +7 (Bence-Bruckler et al, 1998), and d 0 versus d +3 versus d +5 (Bolwell et al, 1998)], but both reported cost savings with the delayed treatment (Legros et al, 1997; Bolwell et al, 1998). On the other hand, a non-randomized study showed significant benefits for early compared with delayed G-CSF (d +1 versus d +4) with regard to neutrophil recovery, length of hospital stay and duration of non-prophylactic antibiotic use, together with an 11% reduction in costs (Colby et al, 1998).

Autologous and allogeneic BMT

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

There are fewer data for the role of CSFs after BMT, but those that are available are positive. In a randomized trial of G-CSF (0, 10 or 30 µg/kg/d) in 54 patients with HD or NHL undergoing autologous BMT, G-CSF treatment was well tolerated and associated with significant reductions in the duration of neutropenia (by up to 16 d) and days with FN (by up to 5 d) (Schmitz et al, 1995b). There were no significant differences between the two doses of G-CSF in this study. In a non-randomized trial in 81 patients undergoing allogeneic BMT, G-CSF started on d +1 after transplant was found to result in a significantly decreased time to engraftment and time from marrow infusion to discharge, together with significantly lower median costs ($3400 difference) (Lee et al, 1998b). In a further randomized study, G-CSF compared with placebo after allogeneic blood stem cell transplantation shortened the time to neutrophil regeneration significantly (Bishop et al, 2000).

Recommendation

CSFs are indicated to accelerate reconstitution after allogeneic and autologous PBPC transplantation or BMT (level Ib, grade A).

References

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices
  • Alegre, A., Tomas, J.F., Martinez-Chamorro, C., Gil-Fernandez, J.J., Fernandez-Villalta, M.J., Arranz, R., Diaz, M.A., Granda, A., Bernardo, M.R., Escudero, A., Lopez-Lorenzo, J.L. & Fernandez-Ranada, J.M. (1997) Comparison of peripheral blood progenitor cell mobilization in patients with multiple myeloma: high-dose cyclophosphamide plus GM-CSF vs G-CSF alone. Bone Marrow Transplantation, 20, 211217.
  • Anaissie, E.J., Vartivarian, S., Bodey, G.P., Legrand, C., Kantarjian, H., Abi-Said, D., Karl, C. & Vadhan-Raj, S. (1996) Randomized comparison between antibiotics alone and antibiotics plus granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived in cancer patients with fever and neutropenia. American Journal of Medicine, 100, 1723.
  • Arbona, C., Prosper, F., Benet, I., Mena, F., Solano, C. & Garcia-Conde, J. (1998) Comparison between once a day vs twice a day G-CSF for mobilization of peripheral blood progenitor cells (PBPC) in normal donors for allogeneic PBPC transplantation. Bone Marrow Transplantation, 22, 3945.
  • Aviles, A., Diaz-Maqueo, J.C., Talavera, A., Nambo, M.J. & Garcia, E.L. (1994) Effect of granulocyte colony-stimulating factor in patients with diffuse large cell lymphoma treated with intensive chemotherapy. Leukemia and Lymphoma, 15, 153157.
  • Bence-Bruckler, I., Bredeson, C., Atkins, H., McDiarmid, S., Hamelin, L., Hopkins, H., Perry, G., Genest, P. & Huebsch, L. (1998) A randomized trial of granulocyte colony-stimulating factor (Neupogen) starting day 1 vs day 7 post-autologous stem cell transplantation. Bone Marrow Transplantation, 22, 965969.
  • Bensinger, W.I., Weaver, C.H., Appelbaum, F.R., Rowley, S., Demirer, T., Sanders, J., Storb, R. & Buckner, C.D. (1995) Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor. Blood, 85, 16551658.
  • Bensinger, W.I., Martin, P.J., Storer, B., Clift, R., Forman, S.J., Negrin, R., Kashyap, A., Flowers, M.E., Lilleby, K., Chauncey, T.R., Storb, R. & Appelbaum, F.R. (2001) Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. New England Journal of Medicine, 344, 175181.
  • Bernasconi, C., Alessandrino, E.P., Bernasconi, P., Bonfichi, M., Lazzarino, M., Canevari, A., Castelli, G., Brusamolino, E., Pagnucco, G. & Castagnola, C. (1998) Randomized clinical study comparing aggressive chemotherapy with or without G-CSF support for high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia evolving from MDS. British Journal of Haematology, 102, 678683.
  • Biesma, B., De Vries, E.G., Willemse, P.H., Sluiter, W.J., Postmus, P.E., Limburg, P.C., Stern, A.C. & Vellenga, E. (1990) Efficacy and tolerability of recombinant human granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related leukopenia and fever. European Journal of Cancer, 26, 932936.
  • Bishop, M.R., Anderson, J.R., Jackson, J.D., Bierman, P.J., Reed, E.C., Vose, J.M., Armitage, J.O., Warkentin, P.I. & Kessinger, A. (1994) High-dose therapy and peripheral blood progenitor cell transplantation: effects of recombinant human granulocyte-macrophage colony-stimulating factor on the autograft. Blood, 83, 610616.
  • Bishop, M.R., Tarantolo, S.R., Geller, R.B., Lynch, J.C., Bierman, P.J., Pavletic, Z.S., Vose, J.M., Kruse, S., Dix, S.P., Morris, M.E., Armitage, J.O. & Kessinger, A. (2000) A randomized, double-blind trial of filgrastim (granulocyte colony-stimulating factor) versus placebo following allogeneic blood stem cell transplantation. Blood, 96, 8085.
  • Bjorkholm, M., Osby, E., Hagberg, H., Kvaloy, S., Teerenhovi, L., Myhre, J., Cavallin-Stahl, E., Holte, H. & Andersson, H. (1999) Randomised trial of r-metHu granulocyte colony stimulating factors as adjunct to CHOP or CNOP treatment of elderly patients with aggressive non-Hodgkin's lymphoma. Proceedings of the American Society of Hematology, 94, 599.
  • Blaise, D., Kuentz, M., Fortanier, C., Bourhis, J.H., Milpied, N., Sutton, L., Jouet, J.P., Attal, M., Bordigoni, P., Cahn, J.Y., Boiron, J.M., Schuller, M.P., Moatti, J.P. & Michallet, M. (2000) Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Societe Francaise de Greffe de Moelle. Journal of Clinical Oncology, 18, 537546.
  • Bohlius, J., Reiser, M., Engert, A. & Group, C.H.M. (2001) Impact of prophylactic use of granulopoiesis-stimulating factors (G-CSF and GM-CSF) in patients with malignant lymphoma undergoing conventional chemotherapy: a comprehensive meta-analysis. Proceedings of the American Society of Hematology, 98, 346a.
  • Bolwell, B.J., Pohlman, B., Andresen, S., Kalaycio, M., Goormastic, M., Wise, K., Wakeling, A., Dannley, R. & Overmoyer, B. (1998) Delayed G-CSF after autologous progenitor cell transplantation: a prospective randomized trial. Bone Marrow Transplantation, 21, 369373.
  • Carella, A.M., Simonsson, B., Link, H., Lennard, A., Boogaerts, M., Gorin, N.C., Tomas-Martinez, J.F., Dabouz-Harrouche, F., Gautier, L. & Badri, N. (1998) Mobilization of Philadelphia-negative peripheral blood progenitor cells with chemotherapy and rhuG-CSF in chronic myelogenous leukaemia patients with a poor response to interferon-alpha. British Journal of Haematology, 101, 111118.
  • Cesana, C., Carlo-Stella, C., Regazzi, E., Garau, D., Sammarelli, G., Caramatti, C., Tabilio, A., Mangoni, L. & Rizzoli, V. (1998) CD34+ cells mobilized by cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) are functionally different from CD34+ cells mobilized by G-CSF. Bone Marrow Transplantation, 21, 561568.
  • Chao, N.J., Schriber, J.R., Grimes, K., Long, G.D., Negrin, R.S., Raimondi, C.M., Horning, S.J., Brown, S.L., Miller, L. & Blume, K.G. (1993) Granulocyte colony-stimulating factor ‘mobilized’ peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy. Blood, 81, 20312035.
  • Clarke, V., Dunstan, F.D. & Webb, D.K. (1999) Granulocyte colony-stimulating factor ameliorates toxicity of intensification chemotherapy for acute lymphoblastic leukemia. Medical Pediatric Oncology, 32, 331335.
  • Colby, C., McAfee, S.L., Finkelstein, D.M. & Spitzer, T.R. (1998) Early vs delayed administration of G-CSF following autologous peripheral blood stem cell transplantation. Bone Marrow Transplantation, 21, 10051010.
  • Dickerson, K. & L.K. (1996) Optimal search strategy for RCTs. Establishing and maintaining an international register of RCTs. In: The Cochrane Library. Update Software, Oxford.
  • Dombret, H., Chastang, C., Fenaux, P., Reiffers, J., Bordessoule, D., Bouabdallah, R., Mandelli, F., Ferrant, A., Auzanneau, G., Tilly, H., Yver, A. & Degos, L. (1995) A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. New England Journal of Medicine, 332, 16781683.
  • Dreger, P., Haferlach, T., Eckstein, V., Jacobs, S., Suttorp, M., Loffler, H., Muller-Ruchholtz, W. & Schmitz, N. (1994) G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: safety, kinetics of mobilization, and composition of the graft. British Journal of Haematology, 87, 609613.
  • Dunlop, D.J., Eatock, M.M., Paul, J., Anderson, S., Reed, N.S., Soukop, M., Lucie, N., Fitzsimmons, E.J., Tansey, P. & Steward, W.P. (1998) Randomized multicentre trial of filgrastim as an adjunct to combination chemotherapy for Hodgkin's disease. West of Scotland Lymphoma Group. Clinical Oncology (Royal College of Radiologists), 10, 107114.
  • Estey, E.H., Thall, P.F., Pierce, S., Cortes, J., Beran, M., Kantarjian, H., Keating, M.J., Andreeff, M. & Freireich, E. (1999) Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/− all-trans retinoic acid +/− granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Blood, 93, 24782484.
  • Faucher, C., Le Corroller, A.G., Blaise, D., Novakovitch, G., Manonni, P., Moatti, J.P. & Maraninchi, D. (1994) Comparison of G-CSF-primed peripheral blood progenitor cells and bone marrow auto transplantation: clinical assessment and cost-effectiveness. Bone Marrow Transplantation, 14, 895901.
  • Freund, D.A. & Dittus, R.S. (1995) Double-blind, placebo-controlled trial of daunorubicin and cytarabine with or without recombinant human granulocyte colony-stimulating factor in elderly patients with acute myeloid leukemia: economic evaluation with attention to inpatient and outpatient resource utilization. Journal of the National Cancer Institute Monograph, 19, 3740 .
  • Fridrik, M.A., Greil, R., Hausmaninger, H., Krieger, O., Oppitz, P., Stoger, M., Klocker, J., Neubauer, M., Helm, W., Pont, J., Fazeny, B., Hudec, M., Simonitsch, I. & Radaszkiewicz, T. (1997) Randomized open label phase III trial of CEOP/IMVP-Dexa alternating chemotherapy and filgrastim versus CEOP/IMVP-Dexa alternating chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). A multicenter trial by the Austrian Working Group for Medical Tumor Therapy. Annals of Hematology, 75, 135140.
  • Garcia-Carbonero, R., Mayordomo, J.I., Tornamira, M.V., Lopez-Brea, M., Rueda, A., Guillem, V., Arcediano, A., Yubero, A., Ribera, F., Gomez, C., Tres, A., Perez-Gracia, J.L., Lumbreras, C., Hornedo, J., Cortes-Funes, H. & Paz-Ares, L. (2001) Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial. Journal of the National Cancer Institute, 93, 3138.
  • Geissler, K., Koller, E., Hubmann, E., Niederwieser, D., Hinterberger, W., Geissler, D., Kyrle, P., Knobl, P., Pabinger, I., Thalhammer, R., Schwarzinger, I., Mannhalter, C., Jaeger, U., Heinz, R., Linkesch, W. & Lechner, K. (1997) Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia – a randomized phase-III study. Blood, 90, 590596.
  • Gerhartz, H.H., Engelhard, M., Meusers, P., Brittinger, G., Wilmanns, W., Schlimok, G., Mueller, P., Huhn, D., Musch, R., Siegert, W., Gerhartz, D., Hartlapp, J.H., Thiel, E., Huber, C., Peschl, C., Spann, W., Emmerich, B., Schadek, C., Westerhausen, M., Pees, H.W., Radtke, H., Engert, A., Terhardt, E., Schick, H., Binder, T., Fuchs, R., Hasford, J., Brandmaier, R., Stern, A.C., Jones, T.C., Ehrlich, H.J., Stein, H., Parwaresch, M., Tiemann, M. & Lennert, K. (1993) Randomized, double-blind, placebo-controlled, phase III study of recombinant human granulocyte-macrophage colony-stimulating factor as adjunct to induction treatment of high-grade malignant non-Hodgkin's lymphomas. Blood, 82, 23292339.
  • Gisselbrecht, C., Haioun, C., Lepage, E., Bastion, Y., Tilly, H., Bosly, A., Dupriez, B., Marit, G., Herbrecht, R., Deconinck, E., Marolleau, J.P., Yver, A., Dabouz-Harrouche, F., Coiffier, B. & Reyes, F. (1997) Placebo-controlled phase III study of lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) in aggressive non-Hodgkin's lymphoma: factors influencing chemotherapy administration. Groupe d'Etude des Lymphomes de l'Adulte. Leukemia and Lymphoma, 25, 289300.
  • Godwin, J.E., Kopecky, K.J., Head, D.R., Willman, C.L., Leith, C.P., Hynes, H.E., Balcerzak, S.P. & Appelbaum, F.R. (1998) A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (9031). Blood, 91, 36073615.
  • Gustavsson, A. (1997) G-CSF (filgrastim) as an adjunct to MOPP/ABVD therapy in Hodgkin's disease. Acta Oncologica, 36, 483488.
  • Hansen, P.B., Johnsen, H.E., Jensen, L., Gaarsdal, E., Simonsen, K. & Ralfkiaer, E. (1995) Priming and treatment with molgramostim (rhGM-CSF) in adult high-risk acute myeloid leukemia during induction chemotherapy: a prospective, randomized pilot study. European Journal of Haematology, 54, 296303.
  • Harousseau, J.L., Witz, B., Lioure, B., Hunault-Berger, M., Desablens, B., Delain, M., Guilhot, F., Le Prise, P.Y., Abgrall, J.F., Deconinck, E., Guyotat, D., Vilque, J.P., Casassus, P., Tournilhac, O., Audhuy, B. & Solary, E. (2000) Granulocyte colony-stimulating factor after intensive consolidation chemotherapy in acute myeloid leukemia: results of a randomized trial of the Groupe Ouest-Est Leucemies Aigues Myeloblastiques. Journal of Clinical Oncology, 18, 780787.
  • Hartmann, L.C., Tschetter, L.K., Habermann, T.M., Ebbert, L.P., Johnson, P.S., Mailliard, J.A., Levitt, R., Suman, V.J., Witzig, T.E., Wieand, H.S., Miller, L.L. & Moertel, C.G. (1997) Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia. New England Journal of Medicine, 336, 17761780.
  • Heil, G., Hoelzer, D., Sanz, M.A., Lechner, K., Liu Yin, J.A., Papa, G., Noens, L., Szer, J., Ganser, A., O'Brien, C., Matcham, J. & Barge, A. (1997) A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood, 90, 47104718.
  • Hellstrom-Lindberg, E., Ahlgren, T., Beguin, Y., Carlsson, M., Carneskog, J., Dahl, I.M., Dybedal, I., Grimfors, G., Kanter-Lewensohn, L., Linder, O., Luthman, M., Lofvenberg, E., Nilsson-Ehle, H., Samuelsson, J., Tangen, J.M., Winqvist, I., Oberg, G., Osterborg, A. & Ost, A. (1998) Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood, 92, 6875.
  • Ho, A.D., Young, D., Maruyama, M., Corringham, R.E., Mason, J.R., Thompson, P., Grenier, K., Law, P., Terstappen, L.W. & Lane, T. (1996) Pluripotent and lineage-committed CD34+ subsets in leukapheresis products mobilized by G-CSF, GM-CSF vs. a combination of both. Experimental Hematology, 24, 14601468.
  • Hohaus, S., Martin, H., Wassmann, B., Egerer, G., Haus, U., Farber, L., Burger, K.J., Goldschmidt, H., Hoelzer, D. & Haas, R. (1998) Recombinant human granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) administered following cytotoxic chemotherapy have a similar ability to mobilize peripheral blood stem cells. Bone Marrow Transplantation, 22, 625630.
  • Klumpp, T.R., Mangan, K.F., Goldberg, S.L., Pearlman, E.S. & Macdonald, J.S. (1995) Granulocyte colony-stimulating factor accelerates neutrophil engraftment following peripheral-blood stem-cell transplantation: a prospective, randomized trial. Journal of Clinical Oncology, 13, 13231327.
  • Kojima, S. (1999) Use of granulocyte colony-stimulating factor for treatment of aplastic anemia. Nagoya Journal of Medical Science, 62, 7782.
  • Kojima, S., Hibi, S., Kosaka, Y., Yamamoto, M., Tsuchida, M., Mugishima, H., Sugita, K., Yabe, H., Ohara, A. & Tsukimoto, I. (2000) Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood, 96, 20492054.
  • Korbling, M., Przepiorka, D., Huh, Y.O., Engel, H., Van Besien, K., Giralt, S., Andersson, B., Kleine, H.D., Seong, D., Deisseroth, A.B., Andreeff, M. & Champlin, R. (1995) Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: potential advantage of blood over marrow allografts. Blood, 85, 16591665.
  • Kumar, M. & Alter, B.P. (1998) Hematopoietic growth factors for the treatment of aplastic anemia. Current Opinions in Hematology, 5, 226234.
  • Lamy, T., Drenou, B., Grulois, I., Leberre, C., Dauriac, C., Amiot, L., Godard, M., Fauchet, R. & LePrise, P.Y. (1994) Improvement of hematologic recovery after high-dose intensification using peripheral blood progenitor cells (PBPC) mobilized by chemotherapy and GM-CSF. Annals of Hematology, 69, 297302.
  • Larson, R.A., Dodge, R.K., Linker, C.A., Stone, R.M., Powell, B.L., Lee, E.J., Schulman, P., Davey, F.R., Frankel, S.R., Bloomfield, C.D., George, S.L. & Schiffer, C.A. (1998) A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia. CALGB Study 9111. Blood, 92, 15561564.
  • Laver, J., Amylon, M., Desai, S., Link, M., Schwenn, M., Mahmoud, H. & Shuster, J. (1998) Randomized trial of r-metHu granulocyte colony-stimulating factor in an intensive treatment for T-cell leukemia and advanced-stage lymphoblastic lymphoma of childhood: a Pediatric Oncology Group pilot study. Journal of Clinical Oncology, 16, 522526.
  • Lee, S.M., Radford, J.A., Dobson, L., Huq, T., Ryder, W.D., Pettengell, R., Morgenstern, G.R., Scarffe, J.H. & Crowther, D. (1998a) Recombinant human granulocyte colony-stimulating factor (filgrastim) following high-dose chemotherapy and peripheral blood progenitor cell rescue in high-grade non-Hodgkin's lymphoma: clinical benefits at no extra cost. British Journal of Cancer, 77, 12941299.
  • Lee, S.J., Weller, E., Alyea, E.P., Ritz, J. & Soiffer, R.J. (1998b) Efficacy and costs of granulocyte colony-stimulating factor in allogeneic T-cell depleted bone marrow transplantation. Blood, 92, 27252729.
  • Legros, M., Fleury, J., Bay, J.O., Choufi, B., Basile, M., Condat, P., Glenat, C., Communal, Y., Tavernier, F., Bons, J.M., Chollet, P., Plagne, R. & Chassagne, J. (1997) rhGM-CSF vs placebo following rhGM-CSF-mobilized PBPC transplantation: a phase III double-blind randomized trial. Bone Marrow Transplantation, 19, 209213.
  • Lepage, E., Gisselbrecht, C., Haioun, C., Sebban, C., Tilly, H., Bosly, A., Morel, P., Herbrecht, R., Reyes, F. & Coiffier, B. (1993) Prognostic significance of received relative dose intensity in non-Hodgkin's lymphoma patients: application to LNH-87 protocol. The GELA (Groupe d'Etude des Lymphomes de l'Adulte). Annals of Oncology, 4, 651656.
  • Linch, D.C., Milligan, D.W., Winfield, D.A., Kelsey, S.M., Johnson, S.A., Littlewood, T.J., Smith, G.M., Hutchinson, R.M., Goldstone, A.H., Fielding, A.K. & Vaughan Hudson, G. (1997) G-CSF after peripheral blood stem cell transplantation in lymphoma patients significantly accelerated neutrophil recovery and shortened time in hospital: results of a randomized BNLI trial. British Journal of Haematology, 99, 933938.
  • Lowenberg, B., Boogaerts, M.A., Daenen, S.M., Verhoef, G.E., Hagenbeek, A., Vellenga, E., Ossenkoppele, G.J., Huijgens, P.C., Verdonck, L.F., Van Der Lelie, J., Wielenga, J.J., Schouten, H.C., Gmur, J., Gratwohl, A., Hess, U., Fey, M.F. & Van Putten, W.L. (1997a) Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. Journal of Clinical Oncology, 15, 34963506.
  • Lowenberg, B., Suciu, S., Archimbaud, E., Ossenkoppele, G., Verhoef, G.E., Vellenga, E., Wijermans, P., Berneman, Z., Dekker, A.W., Stryckmans, P., Schouten, H., Jehn, U., Muus, P., Sonneveld, P., Dardenne, M. & Zittoun, R. (1997b) Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood, 90, 29522961.
  • Maher, D.W., Lieschke, G.J., Green, M., Bishop, J., Stuart-Harris, R., Wolf, M., Sheridan, W.P., Kefford, R.F., Cebon, J., Olver, I., McKendrick, J., Toner, G., Bradstock, K., Lieschke, M., Cruickshank, S., Tomita, D.K., Hoffman, E.W., Fox, R.M. & Morstyn, G. (1994) Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial. Annals of Internal Medicine, 121, 492501.
  • Marsh, J.C. (2000) Hematopoietic growth factors in the pathogenesis and for the treatment of aplastic anemia. Seminars in Hematology, 37, 8190.
  • Mayordomo, J.I., Rivera, F., Diaz-Puente, M.T., Lianes, P., Colomer, R., Lopez-Brea, M., Lopez, E., Paz-Ares, L., Hitt, R., Garcia-Ribas, I., Cubedo, R., Alonso, S. & Cortesfunes, H. (1995) Improving treatment of chemotherapy-induced neutropenic fever by administration of colony-stimulating factors. Journal of the National Cancer Institute, 87, 803808.
  • Meisenberg, B., Brehm, T., Schmeckel, A., Miller, W. & McMillan, R. (1998) A combination of low-dose cyclophosphamide and colony-stimulating factors is more cost-effective than granulocyte-colony-stimulating factors alone in mobilizing peripheral blood stem and progenitor cells. Transfusion, 38, 209215.
  • Michel, G., Landman-Parker, J., Auclerc, M.F., Mathey, C., Leblanc, T., Legall, E., Bordigoni, P., Lamagnere, J.P., Demeocq, F., Perel, Y., Auvrignon, A., Berthou, C., Bauduer, F., Pautard, B., Schneider, P., Schaison, G., Leverger, G. & Baruchel, A. (2000) Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: a randomized trial in very high-risk childhood acute lymphoblastic leukemia. Journal of Clinical Oncology, 18, 15171524.
  • Mitchell, P.L., Morland, B., Stevens, M.C., Dick, G., Easlea, D., Meyer, L.C. & Pinkerton, C.R. (1997) Granulocyte colony-stimulating factor in established febrile neutropenia: a randomized study of pediatric patients. Journal of Clinical Oncology, 15, 11631170.
  • Nademanee, A., Sniecinski, I., Schmidt, G.M., Dagis, A.C., O'Donnell, M.R., Snyder, D.S., Parker, P.M., Stein, A.S., Smith, E.P., Molina, A., Stepan, D.E., Somlo, G., Margolin, K.A., Woo, D., Niland, J.C. & Forman, S.J. (1994) High-dose therapy followed by autologous peripheral-blood stem-cell transplantation for patients with Hodgkin's disease and non-Hodgkin's lymphoma using unprimed and granulocyte colony-stimulating factor-mobilized peripheral-blood stem cells. Journal of Clinical Oncology, 12, 21762186.
  • Ohno, R., Naoe, T., Kanamaru, A., Yoshida, M., Hiraoka, A., Kobayashi, T., Ueda, T., Minami, S., Morishima, Y., Saito, Y., Furusawa, S., Imai, K., Takemoto, Y., Miura, Y., Teshima, H. & Hamajima, N. (1994) A double-blind controlled study of granulocyte colony-stimulating factor started two days before induction chemotherapy in refractory acute myeloid leukemia. Kohseisho Leukemia Study Group. Blood, 83, 20862092.
  • Ossenkoppele, G.J., Van Der Holt, B., Verhoef, G.E., Daenen, S.M., Verdonck, L.F., Sonneveld, P., Wijermans, P.W., Van Der Lelie, J., Van Putten, W.L. & Lowenberg, B. (1999) A randomized study of granulocyte colony-stimulating factor applied during and after chemotherapy in patients with poor risk myelodysplastic syndromes: a report from the HOVON Cooperative Group. Dutch-Belgian Hemato-Oncology Cooperative Group. Leukemia, 13, 12071213.
  • Ottmann, O.G., Hoelzer, D., Gracien, E., Ganser, A., Kelly, K., Reutzel, R., Lipp, T., Busch, F.W., Schwonzen, M., Heil, G., Wandt, H., Koch, P., Kolbe, K., Heyll, A., Bentz, M., Peters, S.D., Iedrich, H., Dethling, J., Meyer, P., Nowrousian, M.R., Loffler, B., Weiss, A., Kneba, M., Foller, A., Graf, M. & Hecht, T. (1995) Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial. Blood, 86, 444450.
  • Ozer, H., Armitage, J.O., Bennett, C.L., Crawford, J., Demetri, G.D., Pizzo, P.A., Schiffer, C.A., Smith, T.J., Somlo, G., Wade, J.C., Wade, J.L., 3rd, Winn, R.J. & Wozniak, A.J. & Somerfield, M.R. (2000) 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. Journal of Clinical Oncology, 18, 35583585.
  • Pavletic, Z.S., Bishop, M.R., Tarantolo, S.R., Martin-Algarra, S., Bierman, P.J., Vose, J.M., Reed, E.C., Gross, T.G., Kollath, J., Nasrati, K., Jackson, J.D., Armitage, J.O. & Kessinger, A. (1997) Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies. Journal of Clinical Oncology, 15, 16081616.
  • Pettengell, R., Gurney, H., Radford, J.A., Deakin, D.P., James, R., Wilkinson, P.M., Kane, K., Bentley, J. & Crowther, D. (1992) Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin's lymphoma: a randomized controlled trial. Blood, 80, 14301436.
  • Pfreundschuh, M., Trumper, L., Kloess, M., Schmitz, N., Schmits, R., Glass, B., Hansenclever, D., Engert, A., Rudolph, C., Illiger, J., Hossfeld, D., Rube, C. & Loeffler, M. (2001) 2 weekly CHOP (CHOP14): the new standard regimen for patients with aggressive non-Hodgkin's lymphoma (NHL) > 60 years of age. Proceedings of the American Society of Hematology, 98, 725a.
  • Pui, C.H., Boyett, J.M., Hughes, W.T., Rivera, G.K., Hancock, M.L., Sandlund, J.T., Synold, T., Relling, M.V., Ribeiro, R.C., Crist, W.M. & Evans, W.E. (1997) Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. New England Journal of Medicine, 336, 17811787.
  • Ravaud, A., Chevreau, C., Cany, L., Houyau, P., Dohollou, N., Roche, H., Soubeyran, P., Bonichon, F., Mihura, J., Eghbali, H., Tabah, I. & Bui, B.N. (1998) Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: results of a randomized phase III trial. Journal of Clinical Oncology, 16, 29302936.
  • Riikonen, P., Saarinen, U.M., Makipernaa, A., Hovi, L., Komulainen, A., Pihkala, J. & Jalanko, H. (1994) Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: a double blind placebo-controlled study in children. Pediatrics Infection and Disease Journal, 13, 197202.
  • Rowe, J.M., Andersen, J.W., Mazza, J.J., Bennett, J.M., Paietta, E., Hayes, F.A., Oette, D., Cassileth, P.A., Stadtmauer, E.A. & Wiernik, P.H. (1995) A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55–70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood, 86, 457462.
  • Schiffer, C.A. (1996) Hematopoietic growth factors as adjuncts to the treatment of acute myeloid leukemia. Blood, 88, 36753685.
  • Schmitz, N., Dreger, P., Suttorp, M., Rohwedder, E.B., Haferlach, T., Loffler, H., Hunter, A. & Russell, N.H. (1995a) Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor). Blood, 85, 16661672.
  • Schmitz, N., Dreger, P., Zander, A.R., Ehninger, G., Wandt, H., Fauser, A.A., Kolb, H.J., Zumsprekel, A., Martin, A. & Hecht, T. (1995b) Results of a randomised, controlled, multicentre study of recombinant human granulocyte colony-stimulating factor (filgrastim) in patients with Hodgkin's disease and non-Hodgkin's lymphoma undergoing autologous bone marrow transplantation. Bone Marrow Transplantation, 15, 261266.
  • Schmitz, N., Linch, D.C., Dreger, P., Goldstone, A.H., Boogaerts, M.A., Ferrant, A., Demuynck, H.M., Link, H., Zander, A. & Barge, A. (1996) Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet, 347, 353357.
  • Schmitz, N., Bacigalupo, A., Hasenclever, D., Nagler, A., Gluckman, E., Clark, P., Bourquelot, P., Greinix, H., Frickhofen, N., Ringden, O., Zander, A., Apperley, J.F., Gorin, C., Borkett, K., Schwab, G., Goebel, M., Russell, N.H. & Gratwohl, A. (1998) Allogeneic bone marrow transplantation vs filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: first results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplantation, 21, 9951003.
  • Shinohara, K. (2000) Overuse of granulocyte colony-stimulating factor in acute myeloid leukemia, aplastic anemia and myelodysplastic syndrome. Internal Medicine, 39, 82.
  • Stone, R.M., Berg, D.T., George, S.L., Dodge, R.K., Paciucci, P.A., Schulman, P., Lee, E.J., Moore, J.O., Powell, B.L. & Schiffer, C.A. (1995) Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. New England Journal of Medicine, 332, 16711677.
  • Storek, J., Gooley, T., Siadak, M., Bensinger, W.I., Maloney, D.G., Chauncey, T.R., Flowers, M., Sullivan, K.M., Witherspoon, R.P., Rowley, S.D., Hansen, J.A., Storb, R. & Appelbaum, F.R. (1997) Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease. Blood, 90, 47054709.
  • Sweetenham, J., Hackshaw, A. & Knight, A. (2000) Evidence-based review and meta-analysis of the use of haemopoietic growth factors (HGFs) in the management of malignant lymphoma (ML). Proceedings of the American Society of Hematology, 96, 139a.
  • Takeshita, A., Ohno, R., Hirashima, K., Toyama, K., Okuma, M., Saito, H., Ikeda, Y., Tomonaga, M. & Asano, S. (1995) [A randomized double-blind controlled study of recombinant human granulocyte colony-stimulating factor in patients with neutropenia induced by consolidation chemotherapy for acute myeloid leukemia (rG.CSF clinical study group)]. Rinsho Ketsueki, 36, 606614.
  • Tarella, C., Castellino, C., Locatelli, F., Caracciolo, D., Corradini, P., Falda, M., Novarino, A., Tassi, V. & Pileri, A. (1998) G-CSF administration following peripheral blood progenitor cell (PBPC) autograft in lymphoid malignancies: evidence for clinical benefits and reduction of treatment costs. Bone Marrow Transplantation, 21, 401407.
  • Thomas, X., Fenaux, P., Dombret, H., Delair, S., Dreyfus, F., Tilly, H., Vekhoff, A., Cony-Makhoul, P., Leblond, V., Troussard, X., Cordonnier, C., De Revel, T., Simon, M., Nicolini, F., Stoppa, A.M., Janvier, M., Bordessoule, D., Rousselot, P., Ffrench, M., Marie, J.P. & Archimbaud, E. (1999) Granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase efficacy of intensive sequential chemotherapy with etoposide, mitoxantrone and cytarabine (EMA) in previously treated acute myeloid leukemia: a multicenter randomized placebo-controlled trial (EMA91 Trial). Leukemia, 13, 12141220.
  • Thompson, J.A., Gilliland, D.G., Prchal, J.T., Bennett, J.M., Larholt, K., Nelson, R.A., Rose, E.H. & Dugan, M.H. (2000) Effect of recombinant human erythropoietin combined with granulocyte/ macrophage colony-stimulating factor in the treatment of patients with myelodysplastic syndrome. GM/EPO MDS Study Group. Blood, 95, 11751179.
  • Usuki, K., Urabe, A., Masaoka, T., Ohno, R., Mizoguchi, H., Hamajima, N., Miyazaki, T., Niitsu, Y., Yoshida, Y., Miura, A., Shibata, A., Abe, T., Miura, Y., Ikeda, Y., Nomura, T., Nagao, T., Saitou, H., Shirakawa, S., Ohkuma, M., Matsuda, T., Nakamura, T., Horiuchi, A., Kuramoto, A., Kimura, I., Irino, S., Niho, Y., Takatsuki, K., Tomonaga, M., Uchino, H. & Takaku, F. (2002) Efficacy of granulocyte colony-stimulating factor in the treatment of acute myelogenous leukaemia: a multicentre randomized study. British Journal of Haematology, 116, 103112.
  • Uyl-de Groot, C.A., Lowenberg, B., Vellenga, E., Suciu, S., Willemze, R. & Rutten, F.F. (1998) Cost-effectiveness and quality-of-life assessment of GM-CSF as an adjunct to intensive remission induction chemotherapy in elderly patients with acute myeloid leukemia. British Journal of Haematology, 100, 629636.
  • Vellenga, E., Uyl-de Groot, C.A., De Wit, R., Keizer, H.J., Lowenberg, B., Ten Haaft, M.A., De Witte, T.J., Verhagen, C.A., Stoter, G.J., Rutten, F.F., Mulder, N.H., Smid, W.M. & De Vries, E.G. (1996) Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related febrile neutropenia. Journal of Clinical Oncology, 14, 619627.
  • Welte, K., Reiter, A., Mempel, K., Pfetsch, M., Schwab, G., Schrappe, M. & Riehm, H. (1996) A randomized phase-III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia. Berlin-Frankfurt-Munster Study Group. Blood, 87, 31433150.
  • Willemze, R., Van Der Lely, N., Zwierzina, H., Suciu, S., Solbu, G., Gerhartz, H., Labar, B., Visani, G., Peetermans, M.E., Jacobs, A., Stryckmans, P., Fenaux, P., Haak, H.L., Ribeiro, M.M., Baumelou, E., Baccarani, M., Mandelli, F., Jaksic, B., Louwagie, A., Thyss, A., Hayat, M., De Cataldo, F., Stern, A.C. & Zittoun, R. (1992) A randomized phase-I/II multicenter study of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for patients with myelodysplastic syndromes and a relatively low risk of acute leukemia. EORTC Leukemia Cooperative Group. Annals of Hematology, 64, 173180.
  • Witz, F., Sadoun, A., Perrin, M.C., Berthou, C., Briere, J., Cahn, J.Y., Lioure, B., Witz, B., Francois, S., Desablens, B., Pignon, B., Le Prise, P.Y., Audhuy, B., Caillot, D., Casassus, P., Delain, M., Christian, B., Tellier, Z., Polin, V., Hurteloup, P. & Harousseau, J.L. (1998) A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM). Blood, 91, 27222730.
  • Yoshida, Y., Nakahata, T., Shibata, A., Takahashi, M., Moriyama, Y., Kaku, K., Masaoka, T., Kaneko, T. & Miwa, S. (1995) Effects of long-term treatment with recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome. Leukemia and Lymphoma, 18, 457463.
  • Zinzani, P.L., Pavone, E., Storti, S., Moretti, L., Fattori, P.P., Guardigni, L., Falini, B., Gobbi, M., Gentilini, P., Lauta, V.M., Bendandi, M., Gherlinzoni, F., Magagnoli, M., Venturi, S., Aitini, E., Tabanelli, M., Leone, G., Liso, V. & Tura, S. (1997) Randomized trial with or without granulocyte colony-stimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade non-Hodgkin's lymphoma. Blood, 89, 39743979.
  • Zittoun, R., Suciu, S., Mandelli, F., De Witte, T., Thaler, J., Stryckmans, P., Hayat, M., Peetermans, M., Cadiou, M., Solbu, G., Petti, M.C. & Willemze, R. (1996) Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. Journal of Clinical Oncology, 14, 21502159.

Appendices

  1. Top of page
  2. Methods
  3. Prophylactic and adjunctive use
  4. Primary prophylaxis
  5. Secondary prophylaxis
  6. Adjunctive use of CSFs
  7. Use Of Csfs In Association With Chemotherapy
  8. Acute myeloid leukaemia
  9. Acute lymphoblastic leukaemia
  10. Myelodysplastic syndromes
  11. Acquired aplastic anaemia and inherited bone marrow failure
  12. Malignant lymphomas
  13. Csfs for pbpc mobilization
  14. Mobilized versus non-mobilized PBPC
  15. Mobilized PBPC versus BMT
  16. Graft-versus-host disease
  17. Csfs after pbsc and marrow transplantation
  18. Autologous PBPC transplantation
  19. Autologous and allogeneic BMT
  20. Disclaimer
  21. References
  22. Appendices

Appendix 1

Summary of ASCO recommendations (2000 update; Ozer et al, 2000).

Primary prophylaxis

Routine use of CSFs not recommended; consider CSFs in high-risk patients, including the elderly.

Secondary prophylaxis

Use of CSFs should be considered in patients with complicated febrile neutropenia.

Chemotherapy

  • •  
    AML: CSF treatment after induction therapy should be used if cost benefits can be shown; CSFs for ‘priming’ are not recommended outside the setting of clinical trials; CSFs are recommended after consolidation chemotherapy.
  • •  
    ALL: G-CSF administration begun after completion of the first few days of chemotherapy of the initial induction or first post-remission course is recommended.
  • •  
    MDS: intermittent use of CSFs may be considered in patients with severe neutropenia and recurrent infection. Prolonged or continuous treatment with CSFs is not recommended.
  • •  
    AA: no specific recommendations.
  • •  
    Lymphoma: no specific recommendations.

PBPC mobilization

Use of CSFs recommended for both patient and donor PBPC mobilization; higher CSF doses may be useful.

Post stem cell transplantation

Use of adjunctive CSFs recommended post-PBPC engraftment and post-autologous or -allogeneic BMT.

Appendix 2

Key to evidence statements and grades of recommendations.

The definitions of the types of evidence and the grading of recommendations used in this guideline originate from the US Agency for Health Care Policy and Research and are set out in the following:

Statements of evidence

  • Ia 
    Evidence obtained from meta-analysis of randomized controlled trials.
  • Ib 
    Evidence obtained from at least one randomized controlled trial.
  • IIa 
    Evidence obtained from at least one well-designed controlled study without randomization.
  • IIb 
    Evidence obtained from at least one other type of well-designed quasi-experimental study.
  • III 
    Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies.
  • IV 
    Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.

Grades of recommendations

  • A Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation.

  • B Requires the availability of well-conducted clinical studies but no randomized clinical trials on the topic of recommendation.

  • C Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality.