Comparison of long-term and short-term administration of itraconazole for primary antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation: a multicenter, randomized, open-label trial

Abstract

Background: The optimal agents and duration of primary antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain a matter of discussion.

Objective: Our objective was to compare the efficacy and safety of long-term and short-term administration of itraconazole (ITCZ) for primary antifungal prophylaxis in allo-HSCT recipients.

Methods: This multicenter, randomized, open-label pilot study was performed in 4 transplant centers in China. Recipients of allo-HSCT without a history of invasive fungal disease (IFD) were randomly assigned to the long-term or the short-term arm. Randomization was carried out by a center computer system. Intravenous ITCZ was given to the patients in both study arms with a loading dose of 400 mg/day for 2 days followed by 200 mg/day until day +14 or when the white blood cell count was >1.0 × 10(9) /L, and then switched to oral ITCZ solution; prophylaxis was continued until day +30 post transplantation in the short-term arm or until day +90 in the long-term arm. The trough serum concentrations of ITCZ also were measured. The primary study endpoint was the incidence of IFD (proven, probable, and possible) within day +90 post transplantation.

Results: A total of 128 recipients were enrolled in this study; 59 of them were randomized to the long-term arm and 62 were randomized to the short-term arm, forming the modified intent-to-treat (mITT) set. The incidence of IFD within day +90, the primary endpoint, was not significantly different between the 2 arms for the mITT set (6.78% in the long-term arm vs. 6.45% in the short-term arm, P = 0.94), or for the per-protocol set (6.90% in the long-term arm vs. 6.67% in the short-term arm, P = 0.96). From day +30 to day +90, the incidence of IFD was 0% and 6.45%, respectively, in the patients with long-term and short-term prophylaxis for the mITT set (P = 0.11). The mean trough serum concentrations of ITCZ was maintained at >500 ng/mL throughout administration. The incidences of withdrawal because of drug-related adverse events in patients with long-term and short-term prophylaxis were 6.78% and 0%, respectively (P = 0.05).

Conclusions: Long-term and short-term administration of ITCZ both seemed effective in preventing IFD in recipients of allo-HSCT. Further study with large sample size should be performed to evaluate this result. ITCZ shows the same pharmacokinetics in recipients of allo-HSCT as in non-recipients.

Trial registration: ClinicalTrials.gov NCT01160952.

Keywords: allogeneic hematopoietic stem cell transplantation; antifungal prophylaxis; itraconazole.