These results suggest that voriconazole is effective antifungal prophylaxis in patients receiving at least 1 mg/kg/day of glucocorticoids for treatment of GVHD. The incidence of proven or probable IFI in our series is comparable to that shown in the report by Ullmann et al in a similar population.12
In that study, the incidence of any IFI in patients receiving posaconazole was 5.3% (incidence of invasive aspergillosis = 2.3%). This compares to 2% and 0%, respectively, in our series. Our results in the comparator group (fluconazole/itraconazole) are also consistent with the findings of Ullmann et al in their fluconazole group: 9% and 7% for IFI and aspergillosis, respectively. In addition, mortality associated with IFI was also comparable to that seen by Ullmann et al. This suggests that voriconazole may be as effective as posaconazole in this setting, a hypothesis that would require a prospective evaluation in order to confirm.
A limitation of retrospective evaluations is the change in practice patterns over time. The two groups differed with respect to age, conditioning regimen intensity, donor source, hematopoietic stem cell source, and initial dose of glucocorticoids used to treat acute GVHD. These differences are reflective of the changes that have occurred in the field of hematopoietic cell transplantation with the use of less intensive conditioning, especially in older patients, peripheral blood becoming the more common source of hematopoietic cells for patients with advanced disease, the increasing availability of HLA-compatible unrelated donors, and the use of lower doses of glucocorticoids for patients with acute GVHD. Three of these factors (age, disease risk, and unrelated donor grafts) are risk factors for IFI,19–21
which would bias treatment effect in favor of the fluconazole/itraconazole group because they were younger, had lower risk disease, and were more likely to have received transplants from related donors. Novel antifungal therapies have also become available over time that could have influenced the comparison of IFI-related mortality. All of the incidences of IFI in this series occurred in patients who received an initial glucocorticoid dose of at least 2 mg/kg/day, suggesting an increased risk of IFI with higher doses of glucocorticoids. Other investigators have also shown this association.19–21
The voriconazole group was more likely to have received lower doses of glucocorticoids, which would bias the treatment effect in its favor. However, when the analysis was restricted to those patients who received at least 2 mg/kg/day of glucocorticoids, the hazard ratio (0.39; 95% confidence interval: 0.08−1.86) was consistent with a protective effect of voriconazole compared to fluconazole/itraconazole, although the subset analysis did not reach significance. The relative impact of other patient characteristics could not be assessed in a multivariate analysis due to the small number of informative cases.
Voriconazole has been compared to fluconazole as prophylaxis beginning in the immediate posttransplant setting in a large, prospective, randomized, double-blind trial.22
In that trial, the cumulative rates of proven, probable, and presumptive IFI were not statistically different in the two arms at 6 months: 10.6% in the fluconazole arm and 6.6% in the voriconazole arm. These proportions are higher than those that we observed, likely due to the inclusion of presumptive infections and longer follow up (6 months versus 100 days) in the prospective study. Microbiologically documented Aspergillus
infections were significantly less frequent in the voriconazole-treated patients, as seen in our series.
In this series, more recently transplanted patients being treated with high-dose glucocorticoid therapy for GVHD appeared to be at a lower risk of developing IFI than in the past. Many factors may have contributed to this lower risk, including the use of reduced intensity conditioning and lower doses of corticosteroids. This retrospective analysis also suggested that giving voriconazole as prophylaxis in this setting had a beneficial effect compared to fluconazole or itraconazole in preventing IFI, especially aspergillosis. A randomized prospective trial would be required to confirm these results.