Use of Granulocyte Colony-Stimulating Factor Following Hematopoietic Cell Transplantation: Does Haste Make Waste?
Authors: Frederick R. Appelbaum
Journal: Journal of Clinical Oncology (2003)

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 casecontrolled 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, diagJOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 3 FEBRUARY 1 2004