The effect of hematopoietic growth factors on the risk of graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis

Abstract

Summary:The effect of hematopoietic growth factors on neutrophil recovery after allogeneic transplantation is well-recognized. Recent laboratory studies demonstrated that these cytokines may also modify T-cell and dendritic cell function, but whether the effect is strong enough to alter the risk of GVHD is unclear. We performed a metaanalysis to determine the effect of G-CSF or GM-CSF on the risk of nonhematopoietic outcomes after allogeneic transplantation. A search of the literature from 1986 to present yielded 18 publications in which data were provided for cohorts receiving growth factor vs either placebo or no therapy. These included nine prospective randomized studies, eight retrospective cohort studies, and one case-control study comprising a total of 1198 patients. The publication types were heterogeneous with regard to demographic and treatment characteristics, although within publications, comparative groups were generally balanced. The pooled risk ratio estimates with use of growth factor was 1.08 (95% CI 0.87-1.33, P ¼ 0.48) for grades 2-4 acute GVHD, 1.22 (95% CI 0.80-1.86, P ¼ 0.99) for grades 3-4 acute GVHD, and 1.02 (95% CI 0.82-1.26, P ¼ 0.87) for chronic GVHD. This analysis did not detect a significant change in the risk of acute or chronic GVHD after allogeneic hematopoietic stem cell transplantation when hematopoietic growth factors were used to shorten the initial period of neutropenia. Bone Marrow Transplantation (2003) 32, 771-775. doi:10.1038/sj.bmt.1704228 Keywords: graft-vs-host disease; G-CSF; GM-CSF; allogeneic G-CSF and GM-CSF are hematopoietic cytokines active in the differentiation and proliferation of neutrophil progenitors as well as the regulation of mature neutrophil activity.Prospective clinical trials and retrospective cohort studies examining the safety and efficacy of these cytokines following allogeneic hematopoietic stem cell transplantation have variably demonstrated several beneficial effects, including reductions in time to hematopoietic recovery, transplant-related toxicity, duration of initial hospitalization, and resource utilization. As a result, judicious use of such growth factors is now considered routine at many allogeneic transplant centers.The understanding of the secondary effects of G-CSF and GM-CSF, especially on the immune system, continues to evolve. In vitro studies of peripheral blood from healthy volunteers showed a Th2 polarization and anti-inflammatory profile in those treated with G-CSF, 23 while GM-CSF induced a profound proinflammatory response, 24 suggesting that when used for acceleration of neutrophil recovery after allogeneic transplantation, these cytokines might alter the risk of GVHD. Since most individual studies of cytokines for engraftment are not powered sufficiently to test for effects on GVHD, we performed a meta-analysis of the published data to determine whether the use of G-CSF and GM-CSF after allogeneic transplantation altered early nonhematopoietic outcomes. Methods Identification of studies and data abstractionA Medline searc...

Optimal use of G-CSF administration after hematopoietic SCT

“…In addition, there was no significant difference in chronic GVHD between patients who received G-CSF vs those who did not. 62 A meta-analysis by Ho et al 59 did not find an increase in the incidence of GVHD with the use of G-CSF. This meta-analysis had a total of 1198 patients with the majority (88%) undergoing BMT.…”

“…Several studies have analyzed the efficacy of using G-CSF compared with control to decrease the number of neutropenic days after allogeneic transplantation in patients receiving either peripheral blood or BM cells. 12,13,[55][56][57][58][59][60][61][62] The outcomes from these studies are summarized in Table 5. Most of these studies included patients with hematological malignancies, whereas some also enrolled patients with solid tumors.…”

“…There was also no difference in the time to plt engraftment, incidence of acute GVHD or post-transplant hospital stay between the early and delayed initiation of G-CSF. [59][60][61]64 As all the three RCTs showed consistent results when comparing the early vs delayed initiation of G-CSF, the evidence was considered to be level 1B because of a combined number of o100 patients in each group. In a study by Lee et al 68 evaluating BMT patients, a significantly higher incidence of hepatic veno-occlusive disease was seen when G-CSF was given on day 0 vs day þ 5 (66.7 vs 40%).…”

Cytokines following SCT: indications and controversies

“…17,18 However, there have been conflicting reports of whether the use of growth factors increases the incidence of acute and chronic GvHD. 19,20 Although the incidence of grade II-IV acute GvHD has been similar for patients receiving allogeneic PBSC when compared with those receiving bone marrow, the incidence of chronic GvHD has been higher in PBSC recipients.…”

Graft-versus-host-disease and granulocyte colony-stimulating factor administration after allogeneic stem cell transplantation

“…Thus, it was concluded that the use of hematopoietic growth factors after allo-SCT did not induce a significant change in the risk of acute or chronic GVHD, when these factors were used to shorten the initial period of neutropenia. 48 Obviously, such study has the strength of the large number of patients included, and the quality of a meta-analysis methodology, that is admitted to allow a relatively good standard of confidence level. In contradiction with the results of this meta-analysis, Remberger et al from a single center study suggested that G-CSF given after allo-SCT using HLAidentical sibling donors increases the risk of grade II-IV acute GVHD.…”