Voriconazole Vs. Itraconazole for Antifungal Prophylaxis in Patients with GVHD: A Randomized Trial

GVHD increases the risk of invasive fungal infections (IFIs). This randomized phase II selection design study was performed to compare the efficacy and safety of voriconazole (VRCZ: n=33) and itraconazole (ITCZ: n=33) in patients with GVHD.

The study was conducted from March 2009 through October 2011. Adult patients who had undergone allogeneic hematopoietic stem cell transplantation were eligible to participate in the study if they had either grade II to IV acute GVHD or chronic GVHD requiring corticosteroid treatment ( PSL>=0.3 mg/kg/day). VRCZ was administered in the form of tablets at a dose of 200 mg twice daily, and ITCZ was administered as oral solution at a dose of 2.5 mg/kg twice daily.

The primary composite endpoint, success of prophylaxis, was defined as survival without proven/probable IFI for 60 days and ability to receive study drug for at least 48 of the 60 days of planned administration.

Age, underlying disease, disease risk, donor type, conditioning intensity and proportion of patients with acute or chronic GVHD were similar between the two groups. The proportion of patients who required dose escalation of the steroid was significantly higher in the VRCZ group (VRCZ 32% vs. ITCZ 9%, P=.03).

The success rate of prophylaxis was comparable between the two groups (VRCZ 88% vs. ITCZ 94%; Difference -6.1%, 95% CI -20 to 7.7%). In the ITCZ group, one patient each developed probable and possible IFI after 42 and 33 days of prophylaxis, respectively. In the VRCZ group, one patient developed possible IFI after 59 days of prophylaxis. There was no fungal-related mortality. The causes of prophylaxis failure included death due to AML, cytopenia, atrial flutter, and catheter-related infection in the VRCZ group (n=4), and probable IFI and withdrawal of consent in the ITCZ group (n=2).

The incidence of SAE (CTCAE v3 grade 3/4) was not different between the two groups (VRCZ 27% vs. ITCZ 21%, P=.77). The most frequent event was liver dysfunction in both groups (VRCZ 18% vs. ITCZ 12%, P=.73), but gastrointestinal events were seen only in the ITCZ group (VRCZ 0% vs. ITCZ 6%, P=.49). A total of 4 patients, exclusively in the ITCZ group, required intravenous administration of the study drug for longer than 14 days (20-23 days), and 3 of the 4 patients had gut acute GVHD. A total of 4 patients received other systemic anti-mold agents during the study period (VRCZ 9% vs. ITCZ 3%, P=.61). However, none received these agents for longer than 14 days (7-10 days) and only one of these patients in the ITCZ group developed possible IFI.

Both the overall survival rate and the cumulative incidence rate of non-relapse mortality were similar at 3 years after randomization between the VRCZ and ITCZ groups (67% vs. 49%, P=.20 by the log-rank test and 14% vs. 26%, P=.31 by the Gray test, respectively).

In conclusion, our study suggested that both VRCZ and ITCZ were feasible for and effective as an antifungal prophylaxis in patients with GVHD.