Editorial

The role of granulocyte-macrophagecolony-stimulating factor in paediatric bonemarrow transplantation

Granulocyte-macrophage colony-stimulating fac-tor (GM-CSF) was the ®rst myeloid growthfactor to be cloned more than a decade ago (1). Ithas potent in vitro and in vivo effects onhaematopoietic progenitors of several lineages:it directly stimulates the proliferation and differ-entiation of granulocyte-macrophage and eosi-nophil progenitors and is able to promote thegrowth of erythroid and megakaryocytic pro-genitors in combination with erythropoietin andinterleukin-3/thrombopoietin, respectively (2±4).This leads in turn to dose-dependent increases inneutrophil, monocyte and eosinophil counts andmore variable and modest effects on red cell andplatelet production (2, 5, 6). Of equal interest,and probably of equal importance, GM-CSF alsohas signi®cant effects on neutrophil and mono-cyte function via its effects on phagocytosis offungi and bacteria, oxidative metabolism, cyto-kine secretion and cytotoxicity (7, 8).

Recognition of these potent biological effectshas led to the rapid introduction of GM-CSF intoclinical practice for a variety of indications. Theseinclude haematopoietic progenitor mobilization,amelioration of chemotherapy-induced and post-bone marrow transplantation (BMT) myelo-suppression, enhancement of antileukaemicchemotherapy, treatment of fungal infectionand several novel applications, e.g. as a vaccineadjunct, as an agent to speed leg ulcer healing andwound healing, and to reduce the severity of post-chemotherapy mucositis (9). However, the preciserole of GM-CSF in clinical medicine, andparticularly in paediatric practice, remains to bede®ned.

The article by Michael Trigg and colleagues inthis issue therefore makes an important contribu-tion to the small volume of literature addressingthe bene®ts and safety of GM-CSF in children(10). Trigg et al. randomized 40 children under-

going allogeneic BMT from partially matchedrelated donors or closely matched unrelateddonors to receive GM-CSF 250 mg/m2 or placeboonce daily from day 0 to day +20 after BMT. Inagreement with most other studies in adults andchildren, they found that GM-CSF signi®cantlyshortened the time to neutrophil recovery(median time to neutrophils $ 500 3 109/l:12 days vs. 14 days). However, GM-CSF hadno effect on any other parameters, including therisk of signi®cant infections, antibiotic use,duration of hospital stay or use of nutritionalsupport. In addition, there was no effect on thenumber of platelet or red blood cell transfusions.Importantly, there was no evidence in this studyof GM-CSF having any signi®cant side-effects inthis setting and, in particular, neither theincidence nor the severity of graft-versus-hostdisease was increased.

Trigg's study therefore shows that even inchildren undergoing `high-risk' allogeneic BMTfrom mismatched donors GM-CSF appears to besafe. This is consistent with other studies inallogeneic BMT in which data from children havebeen included but not separately analyzed (11,12). Taken together, these studies, and others inchildren receiving high-dose chemotherapy (13,14), indicate fairly conclusively that GM-CSF indoses of # 250 mg/m2/day is safe in myelosup-pressed children. What is less clear from thesestudies is whether the effects of GM-CSF onneutrophils and other cells translate to realclinical bene®t in paediatric BMT.

Evidence in support of a useful clinical rolecomes from a number of sources. Nemunaitiset al., in a large randomized study of 109 patients(including 20 children) undergoing allogeneicBMT from HLA-identical siblings, showed thatthe reduction in time to neutrophil recoverymediated by GM-CSF was accompanied both by

Pediatr Transplantation 2000: 4: 86±88

Printed in UK. All rights reserved

Copyright # Munksgaard 2000

Pediatric TransplantationISSN 1397±3142

86

a reduction in the risk of infection (34 vs. 51) andby a reduction in the hospital stay (1 day) (12).The failure of Trigg's study to show such an effectprobably re¯ects the relatively small number ofpatients in the study who received GM-CSF (17children). Nemunaitis et al. also found a sig-ni®cant (p 5 0.005) reduction in the severity ofmucositis (12). A similar ®nding was noted in thenon-randomized trial reported by Gordon et al.,in which they found that children undergoingstem cell transplantation following total bodyirradiation conditioning had a signi®cantlyshorter duration of mucositis when they receivedGM-CSF (12 days vs. 20 days) (15). GM-CSFhas also been shown to reduce mortality owing tofungal infections in patients receiving chemother-apy for acute myeloid leukaemia (AML) (16).Furthermore, preliminary studies indicate that itcan enhance the cytotoxicity of antitumor anti-bodies in refractory neuroblastoma (17) and inAML (8, 18).

Thus, taken together, data from non-rando-mized and from randomized controlled trialsprovide reasonable justi®cation for the routineuse of GM-CSF following allogeneic BMT inchildren. This is in accord with the AmericanSociety of Clinical Oncology guidelines for theuse of haematopoietic growth factors that sup-port the use of GM-CSF or G-CSF to protectagainst febrile neutropenia in children receivingchemotherapy while accepting the paucity ofavailable evidence (5, 19). A ®nal point to note isthat, despite the theoretical attractions of GM-CSF given its effects on neutrophil and monocytefunction, there is as yet no rigorous evidence tosupport the choice of GM-CSF over G-CSF.Data from comparative trials are awaited withinterest.

Irene Roberts, MD1

Mary McCloy MB, ChB

Children's BMT Unit

Department of Haematology

Hammersmith HospitalDu Cane Road

London W12 0NN

UKFax: +44 181 742 9335E-mail: irene.roberts@ic.ac.uk1Correspondent

References

1. WONG GG, WITEK JS, TEMPLE PA, et al. Human GM-CSF: molecular cloning of the complementary DNAand puri®cation of the natural and recombinantproteins. Science 1985: 228: 810±815.

2. METCALF D. The molecular biology and functions of the

granulocyte-macrophage colony-stimulating factors.Blood 1986: 67: 237±245.

3. NEMUNAITIS J. Granulocyte-macrophage colony-stimu-lating factor: a review from preclinical development toclinical application. Transfusion 1993: 33: 70±85.

4. BIRKMANN J, OEZ S, SMETAK M, et al. Effects ofrecombinant human thrombopoietin alone and incombination with erythropoietin and early-acting cyto-kines on human mobilized puri®ed CD34+ progenitorcells cultured in serum-depleted medium. Stem Cells1997: 15: 18±32.

5. ASCO AD HOC COLONY-STIMULATING FACTOR GUIDELINES

EXPERT PANEL. American Society of Clinical Oncologyrecommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practiceguidelines. J Clin Oncol 1994: 12: 2471±2508.

6. GANSERIES A, HEIL G. Use of hematopoietic growthfactors in the treatment of acute myelogenous leukemia.Curr Opin Hematol 1997: 4: 191±195.

7. COLEMAN DL, CHODAKEWITZ JA, BARTISS AL, MELLORS

JW. Granulocyte-macrophage colony-stimulating factorenhances selective effector functions of tissue-derivedmacrophages. Blood 1988: 72: 573±578.

8. WING EJ, MAGEE M, WHITESIDE TL. Recombinanthuman granulocyte/macrophage colony-stimulatingfactor enhances monocyte cytotoxicity and secretionof tumor necrosis factor a and interferon in cancerpatients. Blood 1989: 73: 643±646.

9. ARMITAGE JO. Emerging applications of recombinanthuman granulocyte-macrophage colony-stimulatingfactor. Blood 1998: 92: 4491±4508.

10. TRIGG ME, PETERS C, ZIMMERMAN MB. Administrationof recombinant human granulocyte-macrophage colony-stimulating factor to children undergoing allogeneictransplantation: a prospective, randomized, double-masked, placebo-controlled trial. Pediatr Transplan-tation 2000: 4: 123±131.

11. NEMUNAITIS J, ROSENFELD CS, ASH R, et al. Phase IIIrandomized, double-blind placebo-controlled trial ofrhGM-CSF following allogeneic bone marrow trans-plantation. Bone Marrow Transplant 1995: 15: 949±954.

12. NEMUNAITIS J, ANASETTI C, STORB R, et al. Phase II trialof recombinant human granulocyte-macrophagecolony-stimulating factor in patients undergoing allo-geneic bone marrow transplantation from unrelateddonors. Blood 1992: 79: 2572±2577.

13. FURMAN WL, FAIRCLOUGH DL, HUHN RD, et al.Therapeutic effects and pharmacokinetics of recombi-nant human granulocyte-macrophage colony-stimulat-ing factor in childhood cancer patients receivingmyelosuppressive chemotherapy. J Clin Oncol 1991: 9:1022±1028.

14. SAARINEN UM, HOVI L, RIIKONEN P, et al. Recombinanthuman granulocyte-macrophage colony-stimulatingfactor in children with chemotherapy-induced neutro-penia. Med Pediatr Oncol 1992: 20: 489±496.

15. GORDON B, SPADINGER A, HODGES E, et al. Effect ofgranulocyte-macrophage colony-stimulating factor onoral mucositis after hematopoietic stem-cell transplan-tation. J Clin Oncol 1994: 12: 1917±1922.

16. ROWE JM, RUBIN A, et al. Incidence of infections in adultpatients (.55 years) with acute myeloid leukemiatreated with yeast-derived GM-CSF (sargramostim):results of a double-blind prospective study by theEastern Cooperative Study Group. In: HIDDEMAN W,BUCHNER T, WORMANN B, SCHELLONG L, RITTER J,CREUTZIG U, eds. Acute Leukemias V Experimental

Editorial

87

Approaches and Management of Refractory Disease.Berlin: Springer Verlag, 1996, p. 178.

17. YU AL, BATOVA A, ALVARADO C, et al. Usefulness of achimeric anti-GD2 (ch14.18) and GM-CSF for refrac-tory neuroblastoma: a POG phase II study. Proc AmSoc Clin Oncol 1997: 16: 513a.

18. RICHARD C, BARO J, BELLO-FERNANDEZ C, et al.Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) administration after

autologous bone marrow transplantation for acutemyeloblastic leukemia enhances activated killer cellfunction and may diminish leukemic relapse. BoneMarrow Transplant 1995: 15: 721±726.

19. ASCO AD HOC COLONY-STIMULATING FACTOR GUIDELINES

EXPERT PANEL. Update of recommendations for the useof hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 1996: 14:1957±1960.

Editorial

88