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Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4430-4432 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.225
In Reply:Center for Allogeneic Stem Cell Transplantation and Division of Clinical Immunology, Karolinska University Hospital Huddinge, Stockholm, Sweden Among patients with acute leukemia in Europe who have undergone allogeneic hematopoietic stem-cell transplantation (HSCT), 28% of bone marrow transplant recipients and 40% of peripheral-blood stem-cell transplant recipients received granulocyte colony-stimulating factor (G-CSF) as prophylaxis after transplantation.1 This took place despite no large-scale, solid prospective studies that showed a clinical benefit of using G-CSF after HSCT, either in the short-term or long-term, in regards to morbidity or survival. Some studies showed that patients receiving G-CSF had a faster engraftment of absolute neutrophil count (ANC), though neither a reduction in infections nor an improvement in transplant-related mortality (TRM) was reported.2-5 As a matter of fact, a study by Schriber et al reported a trend toward increased mortality in recipients of grafts from unrelated donors who were given G-CSF.3 Similar data with a trend toward higher TRM and poorer 100-day overall survival were also reported in a double-blind, randomized, placebo-controlled study of granulocyte-macrophage colony-stimulating factor (GM-CSF) by Anasetti et al.6 This study is highlighted in the Letter to the Editor by Dr Mehta. It is, however, worth pointing out that to date this study has only been presented as an abstract and has not been published. During a period of 9 years, 356 HSCT patients at our unit were given G-CSF as prophylaxis. These patients were given G-CSF based on the reports of a faster engraftment of ANC, with the hope of an earlier discharge and fewer infectious complications.2-5 In 1993, we participated in a randomized, double-blind, multicenter, placebo-controlled trial comparing G-CSF with placebo in patients with acute lymphoblastic leukemia or lymphoblastic lymphoma in complete remission treated with high-dose chemotherapy, total-body irradiation, and HSCT. Eight centers participated in the study: Munich and Berlin, Germany; Helsinki, Finland; two centers from Riyadh, Saudi Arabia; Genoa, Italy; Brussels, Belgium; and our unit at Stockholm, Sweden. The study, G-13043-A, was conducted by Roche (Basel, Switzerland) and Amgen (Thousand Oaks, CA). This was a "good clinical practice" study. Random assignment of patients was performed by the International Institute for Drug Development in Brussels, Belgium, and all the case report forms were checked and monitored accordingly. The study was performed between April 1993, and October 1996, with a minimum follow-up of 2 years, and was supposed to be summarized in 1999. In 1994, we also started a study in HSCT recipients of unrelated bone marrow to find out whether G-CSF treatment could be delayed after transplantation, but still have an enhancing effect on engraftment of ANC.7 The initial plan was to have one group with no treatment and compare their results with G-CSF, starting on either day 5 or day 10 after transplantation. We contacted Roche and Amgen to get a free drug for this investigator-driven study. They replied that we would get free filgrastim for two arms, provided that G-CSF was given from day 0 in one arm and that the controls without G-CSF were excluded. For financial reasons and because of the limited number of transplantations, the arm without treatment was excluded. This study compared G-CSF given on days 0, +5, and +10, respectively, and the patients reached an ANC of > 0.5 x 109/L at a median of 17, 16, and 16 days after HSCT, respectively.7 This was sooner than the 21 days in a comparable retrospective control group of patients not treated with G-CSF (P = .004). Based on these results, we decided to treat all our HSCT patients from day +10 with G-CSF, which was given intravenously at a dose of 5 µg/kg daily until ANC reached > 0.5 x 109/L for 2 consecutive days. In our experience, we have always had a relatively low incidence of grade II-IV acute graft-versus-host disease (GVHD).8 In recipients of grafts from HLA-identical siblings, the probability of grade II-IV acute GVHD was 11%, whereas it was 15% among recipients of grafts from unrelated donors.8 The reason for the low incidence of acute GVHD among recipients of grafts from HLA-identical siblings was the early institution of prednisolone right from grade I acute GVHD.9 The reason for the low incidence of acute GVHD among recipients of unrelated grafts was genomic HLA-matching and the use of antithymocyte globulin during conditioning.10,11 However, in later years we saw an increased proportion of patients with moderate-to-severe acute GVHD. We continuously performed production controls of outcome in our patients to ensure low TRM and the best possible long-term overall survival and leukemia-free survival.12 Subsequently, we did an analysis of the patients with hematologic malignancies who underwent transplantations from HLA-identical sibling between 1993 and 2001.13 Of the 155 patients, 66 (43%) received G-CSF after HSCT. Those given G-CSF had a significantly shorter time to an ANC of > 0.5 x 109/L (P < .001). However, patients treated with G-CSF had a significantly higher incidence of grade II-IV acute GVHD than those not given this treatment, 34% versus 9% (odds ratio, 3.82; P < .01). Following this study, we immediately stopped using G-CSF as prophylaxis after HSCT in all of our patients. Before this study was completed, I contacted Roche and Amgen on several occasions to find out what had happened to our double-blind, randomized study, G-13043-A. However, several letters, emails, and phone calls to them resulted in their denial of the existence of the study, referral to other persons, or most commonly, no response at all. We analyzed sera for content of G-CSF among the patients from our unit who participated in the G-13043-A study. This enabled us to establish which patients were and which were not given G-CSF. I also wrote to the other centers participating in the G-13043-A trial, offering them an opportunity to retrospectively analyze the sera in the patients who participated in the trial in order to evaluate the outcome in these patients. At the time of publication, I have only gotten replies from three centers. I also proposed a study to the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). This study showed that patients with acute leukemia receiving bone marrow from HLA-identical sibling donors and treated with G-CSF had an increased risk of acute and chronic GVHD and increased TRM, and a decrease in overall survival and leukemia-free survival.1 However, these findings are in contrast to a meta-analysis of 18 studies, which included nine prospective randomized trials, eight retrospective cohort studies, and one case-matched study.14 The meta-analysis found no evidence of an increase in acute or chronic GVHD or TRM after using G-CSF. However, a recent study from the Center for International Bone and Marrow Transplant Research (CIBMTR) of children and adolescents undergoing bone marrow or peripheral-blood stem-cell transplantation for leukemia found that G-CSF after transplantation was associated with increased TRM, poor overall survival, and poor leukemia-free survival in multivariate analysis.15 All studies seem to agree that G-CSF significantly accelerates myeloid recovery, though several showed that this is at the cost of delayed platelet engraftment.1,16,17 In the reports to the EBMT, the vast majority of patients were treated with G-CSF, and only a few patients were treated with GM-CSF.1 Therefore, no analysis of the effects of GM-CSF could be performed. Hence the report by Dr Mehta is welcome, highlighting and summarizing the experience of GM-CSF given as prophylaxis after HSCT. I also agree that the use of GM-CSF or G-CSF should be confined to patients who experience delayed engraftment. Among the patients (n = 215) in the EBMT study who were given G-CSF for graft failure more than 14 days after transplantation, acute GVHD grade II-IV occurred only in 15% of the patients, and chronic GVHD in 27%.1 In these patients, 5-year TRM was 31%, overall survival, 45%, and leukemia-free survival, 40%. These data possibly suggest that G-CSF can be given for graft failure without a high risk of GVHD. Such patients are rare, and it may therefore be difficult to collect a sufficient number of patients for a meaningful prospective study, even in a multicenter trial. I agree with Dr Mehta that there are more vital issues to address regarding HSCT. Some lessons may be learned from this report. Before including new treatment modalities in HSCT protocols, appropriate safety studies and proper prospective randomized studies enrolling enough patients to evaluate long-term TRM and overall survival are necessary. Furthermore, we have to rely on academic nonprofit studies. Double-blind company-driven good clinical practice studies may disappear if data are in conflict with the interests of the stockholders. Not only at our unit, but also in one third of the European units, G-CSF was used as prophylaxis after HSCT, and we were encouraged only by a faster engraftment of ANC, with insufficient data to evaluate more vital end points. Retrospective analyses of large registries of patients, like those at EBMT and CIBMTR, will eventually help us understand the long-term ramifications of changing the regimen. 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 FR: Allogeneic marrow transplantation and the use of hematopoietic growth factors. Stem Cells 13:344-350, 1995[Medline]
3. Schriber JR, Chao NJ, Long GD, et al: Granulocyte colony-stimulating factor after allogeneic bone marrow transplantation. Blood 84:1680-1684, 1994 4. 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]
5. 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 6. Anasetti C, Anderson G, Appelbaum FR, et al: Phase III study of rhGM-CSF in allogeneic marrow transplantation from unrelated donors. Blood 82:454a, 1993 (suppl 1; abstr) 7. Hägglund H, Ringdén O, Öman S, et al: A prospective randomized trial of Filgrastim (r-metHuG-CSF) given at different times after unrelated bone marrow transplantation. Bone Marrow Transplant 24:831-836, 1999[CrossRef][Medline] 8. Ringdén O, Remberger M, Persson U, et al: Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 15:619-625, 1995[Medline] 9. Ringdén O, Båryd I, Gahrton G, et al: Early treatment and prophylaxis of graft-versus-host disease using prednisolone, in Touraine JL, Gluckman E, Griscelli C (ed): Excerpta Medica: Bone marrow transplantation in Europe Vol II. Amsterdam, the Netherlands, Elsevier, 1981, pp 171-177 10. Ringdén O, Remberger M, Carlens S, et al: Low incidence of acute graft-versus-host disease, using unrelated HLA-A, -B and -DR compatible donors and conditioning including anti-T-cell antibodies. Transplantation 66:620-625, 1998[CrossRef][Medline] 11. Remberger M, Storer B, Ringdén O, et al: Association between pretransplant thymoglobulin and reduced non-relapse mortality rate after marrow transplantation from unrelated donors. Bone Marrow Transplant 29:391-397, 2002[CrossRef][Medline] 12. Ringdén O, Aschan J, Boström L, et al: Allogeneic bone marrow transplantations at Huddinge Hospital and strategies to improve survival, in Terasaki P (ed): Clinical Transplants. Los Angeles, CA, UCLA, 1990, pp 175-188 13. Remberger M, Naseh N, Aschan J, et al: G-CSF given after haematopoietic stem cell transplantation using HLA-identical sibling donors is associated to a higher incidence of acute GVHD II-VI. Bone Marrow Transplant 32:217-223, 2003[CrossRef][Medline] 14. 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] 15. Eapen M, Horowitz MM, Klein JP, et al: Increased chronic graft-versus-host disease and mortality after peripheral-blood stem cell transplants in children and adolescents with acute leukemia. J Clin Oncol (in press) 16. Ringdén O, Barrett AJ, Zhang M-J, et al: Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses. Br J Haematol 121:874-885, 2003[CrossRef][Medline]
17. Kawano Y, Takaue Y, Mimaya J, et al: Marginal benefit/disadvantage of granulocyte colony-stimulating factor therapy after autologous blood stem cell transplantation in children: Results of a prospective randomized trial—The Japanese Cooperative Study Group of PBSCT. Blood 92:4040-4046, 1998
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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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