|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2004.11.963 on December 22 2003 © 2004 American Society of Clinical Oncology.
Use of Granulocyte Colony-Stimulating Factor Following Hematopoietic Cell Transplantation: Does Haste Make Waste?Fred Hutchinson Cancer Research Center, Seattle, WA Granulocyte colony-stimulating factor (G-CSF) is sometimes used immediately following allogeneic hematopoietic cell transplantation (HCT) in an effort to hasten engraftment, thereby reducing complications associated with pancytopenia. In this issue of the Journal of Clinical Oncology, Ringden et al [1] from the European Group for Blood and Marrow Transplantation, present a retrospective analysis of the use of G-CSF after allogeneic HCT, demonstrating that the use of G-CSF in this setting shortens the period of neutropenia but prolongs the period of thrombocytopenia. Much more worrisome is their observation that, when marrow is the source of stem cells, post-transplant G-CSF increases both the incidence of acute and chronic graft-versus-host disease (GVHD) and treatment-related mortality, resulting in lower leukemia-free and overall survival rates. These deleterious effects of G-CSF were not observed when mobilized peripheral blood was the source of stem cells. These observations are, of course, reason for concern. But before announcing a final verdict, both the Ringden et al study [1] and other published literature deserve close scrutiny as there have been a substantial number of previous studies examining the use of hematopoietic growth factors following allogeneic transplantation. A meta-analysis of 18 studies was recently conducted that included nine prospective randomized trials, eight retrospective cohort studies, and one case-control study [2-22]. This analysis included 1,198 patients, most of whom (898 patients) were involved in studies of G-CSF and most (1,056 patients) received marrow as a source of stem cells. Similar to the study by Ringden et al, the meta-analysis showed that use of growth factors significantly accelerated myeloid recovery. But in contrast to the Ringden et al article, the meta-analysis found no evidence for an increase in acute or chronic GVHD, and no evidence for an increase in treatment-related mortality. It is difficult to reconcile the contrasting conclusions of these two analyses. Both have the strength of large numbers, with over 1,000 patients represented in each. Both are weakened by their retrospective nature. When considering both analyses, one would, of course, like to be reassured that the patients who did or did not receive growth factor were comparable. Insufficient data are presented in the meta-analysis to reach such a conclusion, and the fact that the individual components of the meta-analysis were randomized trials and case-controlled or cohort studies does not guarantee that, in aggregate, imbalances do not exist. In the study presented in this issue of the Journal of Clinical Oncology, there were clear imbalances in the patient groups. There were significant differences in patient and donor age, diagnosis, disease status, and method of GVHD prophylaxis. Specifically, although the group receiving G-CSF was younger, they also were significantly more likely to have advanced stage disease and receive single agent GVHD prophylaxis rather than the more effective combination of cyclosporine plus methotrexate. Although the authors state that they used a Cox proportional hazard regression model to account for these imbalances, there is no description of how this was done. Ideally, one would create a base model from all variables other than the use of growth factors and then test how growth factor treatment affected this base model. Perhaps the authors did this, but if G-CSF was included before some other variables, there is a chance that G-CSF use—if correlated with other variables—would override their effects on outcome. Equally concerning is how the authors included the "center" effect in their modeling. As patients came from 155 different transplant teams, it is obviously not possible to adjust for each individual team in the regression models. While this concern might seem trivial to some, diagnosing GVHD is not straightforward. Surprising differences have been noted between centers using identical regimens in similar groups of patients, likely as a result of the vigor with which a GVHD diagnosis is pursued and the manner in which ambiguous clinical and laboratory findings are interpreted. Additional statistical analyses could help bolster the authors' conclusions. An analysis restricted to patients who received optimal GVHD prophylaxis would be of interest. Similarly, it would be important to see if their conclusions held if the analysis was restricted to those centers that included patients who either received or did not receive growth factors, and excluded centers where patients received no growth factors. Even with these additional analyses, however, reconciling the results of the current study with the large meta-analysis will likely remain difficult. It is a shame that we still are unsure of the effects of growth factors post-allogeneic transplantation more than a decade after their introduction into the clinic. This is particularly true in regard to their effect on GVHD. There are a number of reasons for this. First, our understanding of GVHD in animal models is enormous, but our understanding of GVHD in humans remains much more limited. Second, GVHD is a difficult disease to diagnose and, although efforts are being made to improve the situation, it is challenging to achieve uniformity in GVHD diagnosis among treatment sites. Finally—and here we have ourselves to blame—there have been far too many small, undersized studies both conducted and published, and far too few randomized trials of sufficient size to address the effects of growth factors, among other transplantation-related issues. The recent creation of the Bone Marrow Transplant Clinical Trials Network may hopefully help remedy this situation. Given the available conflicting data, what is the role of growth factors after allogeneic bone marrow transplantation? While the effects of G-CSF after marrow transplantation may not be as deleterious as suggested in the paper by Ringden et al [1], the beneficial effects also seem relatively restricted. Thus, despite the limitations of the current article, the authors' conclusion that "there is little reason to treat allogeneic bone marrow transplant patients with G-CSF as prophylaxis after treatment" seems reasonable. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Ringden O, Labopin M, Gorin N-C, et al: Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-vs-host disease and death. J Clin Oncol 22:416-423, 2004 2. Ho VT, Mirza NQ, del Junco D, et al: The effect of hematopoietic growth factors on the risk of graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: A meta-analysis. Bone Marrow Transplant 32:771-775, 2003[CrossRef][Medline]
3. Kitayama H, Ishikawa J, Yamagami T, et al: Granulocyte colony-stimulating factor in allogeneic bone marrow transplantation. Jpn J Clin Oncol 19:367-372, 1989 4. Masaoka T, Moriyama Y, Kato S-I, et al: A double-blind controlled study of KRN 8601 (G-CSF) in patients who received allogeneic bone marrow transplantation. Transplant Now 3:233-239, 1990 5. Asano S, Masaoka T, Takaku F: Clinical effect of recombinant human granulocyte colony-stimulating factor in bone marrow transplantation. The Japan rhG-CSF Clinical Study Group. Gan To Kagaku Ryoho 17:1201-1209, 1990[Medline] 6. Powles R, Smith C, Milan S, et al: Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukemia: Double-blind, placebo-controlled trial. Lancet 336:1417-1420, 1990[CrossRef][Medline]
7. De Witte T, Gratwohl A, Van Der Lely N, et al: Recombinant human granulocyte-macrophage colony-stimulating factor accelerates neutrophil and monocyte recovery after allogeneic T-cell-depleted bone marrow transplantation. Blood 79:1359-1365, 1992
8. Schriber JR, Chao NJ, Long GD, et al: Granulocyte colony-stimulating factor after allogeneic bone marrow transplantation. Blood 84:1680-1684, 1994 9. Gisselbrecht C, Prentice HG, Baciagalupo A, et al: Placebo-controlled phase III trial of lenograstim in bone-marrow transplantation. Lancet 343:696-700, 1994[CrossRef][Medline]
10. Hiraoka A, Masaoka T, Mizoguchi H, et al: Recombinant human non-glycosylated granulocyte-macrophage colony-stimulating factor in allogeneic bone marrow transplantation: Double-blind placebo-controlled phase III clinical trial. Jpn J Clin Oncol 24:205-511, 1994 11. Nemunaitis J, Rosenfeld CS, Ash R, et al: Phase III randomized, double-blind placebo-controlled trial of GM-CSF following allogeneic bone marrow transplantation. Bone Marrow Transplant 15:949-954, 1995[Medline] 12. Martin-Agarra S, Bishop MR, Tarabtolo S, et al: Hematopoietic growth factors after HLA-identical allogeneic bone marrow transplantation in patients treated with methotrexate-containing graft-vs-host disease prophylaxis. Exp Hematol 23:1503-1508, 1995[Medline] 13. Locatelli F, Pession A, Zecca M, et al: Use of recombinant human granulocyte colony-stimulating factor in children given allogeneic bone marrow transplantation for acute or chronic leukemia. Bone Marrow Transplant 17:31-37, 1996[Medline] 14. Xiaojun H, Nailan G, Yunming F, et al: Recombinant human granulocyte colony-stimulating factor after allogeneic bone marrow transplantation. Chinese Med J 109:827-831, 1996 15. Saarinen UM, Hovi L, Juvonen E, et al: Granulocyte colony-stimulating factor after allogeneic and autologous bone marrow transplantation in children. Med Pediatr Oncol 26:380-386, 1996[CrossRef][Medline]
16. Lee SJ, Weller E, Alyea IP, et al: Efficacy and costs of granulocyte colony-stimulating factor in allogeneic T-cell depleted bone marrow transplantation. Blood 92:2725-2729, 1998 17. Berger C, Bertz H, Schmoor C, et al: Influence of recombinant human granulocyte colony-stimulating factor (filgrastim) on hematopoietic recovery and outcome following allogeneic bone marrow transplantation (BMT) from volunteer unrelated donors. Bone Marrow Transplant 23:983-990, 1999[CrossRef][Medline]
18. Madero L, Diaz MA, Ortega JJ, et al: Recombinant human granulocyte-macrophage colony-stimulating factor accelerates engraftment kinetics after allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia. Haematologica 84:133-137, 1999
19. 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
20. 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 21. Trigg ME, Peters C, Zimmerman MB: Administration of recombinant human granulocyte-macrophage colony-stimulating factor to children undergoing allogeneic marrow transplantation: A prospective, randomized, double-masked, placebo-controlled trial. Pediatr Transplant 4:123-131, 2000[CrossRef][Medline] 22. 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]
Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
