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Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4429-4430 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.105
Myeloid Growth Factors Should Not Be Administered Routinely After Allogeneic Hematopoietic Stem-Cell TransplantationDivision of Hematology/Oncology, Northwestern University Feinberg School of Medicine, The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL To the Editor: A recent analysis from the European Group for Blood and Marrow Transplantation1 and the accompanying editorial2 rightly caution against the routine use of granulocyte colony-stimulating factor (G-CSF) after allogeneic bone marrow transplantation (BMT) to accelerate neutrophil recovery because of increased likelihood of an adverse outcome in patients receiving G-CSF. However, neither article commented on the appropriateness of the routine use of granulocyte-macrophage colony-stimulating factor (GM-CSF) after allogeneic BMT, nor of the use of either G-CSF or GM-CSF after allogeneic blood stem-cell transplantation (BSCT). In a blinded study, the Royal Marsden Hospital group showed that allogeneic BMT patients who were treated with GM-CSF (molgramostim) had a longer duration of fever than patients treated with placebo.3 Long-term follow-up of this small study showed no survival difference between the groups, highlighting the lack of benefit of GM-CSF administration.4 More alarmingly, a double-blind, randomized placebo-controlled study of GM-CSF (sargramostim) in patients receiving BMT from unrelated donors showed a trend toward higher treatment-related mortality and poorer 100-day survival in the GM-CSF recipients.5 No further follow-up details have been published on this study presented in abstract form. GM-CSF (molgramostim more than sargramostim) can cause fluid retention, fever, and skin rash in some patients, phenomena that are undesirable in patients that have had hematopoietic allograft, and that can cloud the clinical picture, including the diagnosis of graft-versus-host disease. Our own experience with molgramostim3,4 led us to eliminate the routine use of myeloid growth factors from clinical practice, including in a subsequent randomized study showing superiority of allogeneic BSCT over BMT.6 Although the European Group for Blood and Marrow Transplantation data do not suggest any detrimental effects of G-CSF given early after allogeneic BSCT, the obvious lack of any survival benefit 1,7-9 must surely bring the practice of giving G-CSF after allogeneic BSCT into question.
Should myeloid growth factors be used at all after a hematopoietic allograft, irrespective of whether the stem cells are derived from bone marrow or blood? We have shown that in patients undergoing allogeneic BMT, leukopenia correlates strongly with adverse outcome.10 Figure 1 shows that the likelihood of transplant-related mortality is dramatically higher in patients with lower leukocyte counts than in those with higher leukocyte counts between days 14 and 22 after BMT. These data suggest that the most appropriate use of myeloid growth factors may be in allograft recipients with leukopenia persisting for 3 weeks after transplantation. Our current policy is to start G-CSF only if the total leukocyte count is
I think it is important to categorically state that there is no evidence to support the routine use of myeloid growth factors after allogeneic transplantation of blood- or marrow-derived stem cells. The use of myeloid growth factors should be confined to patients experiencing delayed engraftment. Is there a place for a controlled study of the use of myeloid growth factors after allogeneic BSCT, performed optimally with methotrexate-containing graft-versus-host disease prophylaxis,2,11 to demonstrate their safety (or, unhappily, the lack of it)? With the number of vital issues to be addressed in the field of hematopoietic allografts, I do not believe this question is sufficiently high priority. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
REFERENCES
1. Ringdén O, Labopin M, Gorin NC, et al: Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: A study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 22:416-423, 2004
2. Appelbaum F: Use of granulocyte colony-stimulating factor following hematopoietic cell transplantation: Does haste make waste? J Clin Oncol 22:390-391, 2004 3. Powles R, Smith C, Milan S, et al: Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: Double-blind, placebo-controlled trial. Lancet 336:1417-1420, 1990[CrossRef][Medline] 4. Singhal S, Powles R, Treleaven J, et al: Long-term safety of GM-CSF (molgramostim) administration after allogeneic bone marrow transplantation for hematologic malignancies: Five-year follow-up of a double-blind randomized placebo-controlled study. Leuk Lymphoma 24:301-307, 1997[Medline] 5. Anasetti C, Anderson G, Appelbaum FR, et al: Phase III study of rhGM-CSF in allogeneic marrow transplantation from unrelated donors. Blood 82 (suppl 1):454a, 1993 (abstr) 6. Powles R, Mehta J, Kulkarni S, et al: Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: A randomised trial. Lancet 355:1231-1237, 2000[CrossRef][Medline]
7. Bishop MR, Tarantolo SR, Geller RB, et al: A randomized, double-blind trial of filgrastim (granulocyte colony-stimulating factor) versus placebo following allogeneic blood stem cell transplantation. Blood 96:80-85, 2000
8. Przepiorka D, Smith TL, Folloder J, et al: Controlled trial of filgrastim for acceleration of neutrophil recovery after allogeneic blood stem cell transplantation from human leukocyte antigen-matched related donors. Blood 97:3405-3410, 2001 9. Ozcan M, Ustun C, Akcaglayan E, et al: Recombinant human granulocyte colony-stimulating factor (rh-G-CSF) may accelerate hematopoietic recovery after HLA-identical sibling allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 27:499-505, 2001[CrossRef][Medline] 10. Mehta J, Powles R, Singhal S, et al: Early identification of patients at risk of death due to infections, hemorrhage, or graft failure after allogeneic bone marrow transplantation on the basis of the leukocyte counts. Bone Marrow Transplant 19:349-355, 1997[CrossRef][Medline]
11. Mehta J, Singhal S: Chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell transplantation: A little methotrexate goes a long way. J Clin Oncol 20:603-604, 2002
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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0.2 x 109/L on day 14 or 
