A pilot study of targeted itraconazole prophylaxis in patients with graft-versus-host disease at high risk of invasive mould infections following allogeneic stem cell transplantation

Abstract

Summary:Patients with severe graft-versus-host disease (GVHD) requiring intensive immunosuppression are at high risk of invasive mould infections (IMI). Prophylaxis with an active, oral antifungal agents with reliable absorption in this context is desirable. A total of 44 patients at high risk of post-engraftment IMI received itraconazole solution 2.5 mg/kg b.d. as prophylaxis. Two of the first nine patients, in whom bioavailability was compromised due to significant vomiting and/or diarrhoea, died of probable or proven invasive aspergillus. None of the subsequent 35 patients, some of whom had severe gut GVHD and who received liposomal amphotericin B prophylaxis until itraconazole was reliably tolerated and absorbed, developed IMI. The overall incidence of IMI was substantially lower than in historical controls. Itraconazole was generally well tolerated, with five patients (11%) ceasing the drug due to intolerance or disturbed liver function. Targeted prophylaxis with oral or parenteral antifungal agents in high-risk allograft recipients appears to be effective in reducing the incidence of IMI. GVHDInvasive mould infections (IMI), particularly with aspergillus species, occur in up to 11% of patients after allogeneic BMT and may be increasing in incidence due to more invasive transplantation procedures in higher risk patients. 1 Characteristically, there is a bimodal pattern of IMI: an early peak during the initial period of neutropenia after conditioning and a late peak around 2-5 months post transplant, 2-4 the latter now comprising the majority of infections. Risk factors for later onset IMI include T-cell depletion, graft-versus-host disease (GVHD), use of highdose corticosteroids, CMV disease and neutropenia. 2,3,5,6 Risk factors for IMI and its incidence appear similar after nonmyeloablative conditioning. 7 Corticosteroids contribute to the risk of IMI independently of GVHD due to complex immunobiological dysregulatory effects; 8 both the duration and dose of corticosteroids are important. 2,9,10 In our institution, the overall incidence of IMI in allograft recipients from 1991 to 1998 was 8%, 11 rising to 20% in those with grades III-IV acute GVHD. 12 An analysis of risk factors for post-engraftment IMI identified prolonged (42 weeks) use of 40.25 mg/kg/day of prednisolone or equivalent corticosteroid as a major risk factor. 12 In order to reduce this incidence, in 1998, our unit examined available prophylactic fungal strategies. Various amphotericin B-based approaches such as low-dose IV 6,13 or inhaled 14 amphotericin B or liposomal amphotericin B 15 had been examined as prophylaxis with either negative or inconclusive results. Important problems with these strategies included the high cost of liposomal amphotericin B, the impracticality of prolonged parenteral delivery in the outpatient setting and renal toxicity.Key features of an ideal strategy included availability of an oral preparation with reliable and good bioavailability, activity against aspergillus and sufficient tolerability to enable admini...

Antifungal prophylaxis in adult stem cell transplantation and haematological malignancy

“…This risk‐adjusted approach has practical implications for clinicians. Most centres, including those in Australia, report that pre‐engraftment, invasive mould infections are rare; most infections occur in the late post‐transplant period, usually in the context of grade 3–4 GVHD 3,4,25–29 …”

“…Most centres, including those in Australia, report that pre-engraftment, invasive mould infections are rare; most infections occur in the late post-transplant period, usually in the context of grade 3-4 GVHD. 3,4,[25][26][27][28][29] Ullmann et al, instituted prophylaxis as soon as GVHD (of grade 2 or greater severity or meeting the criteria for chronic extensive) was diagnosed. 18 This study demonstrated a reduction in IFI in patients receiving posaconazole compared with those receiving fluconazole or itraconazole (level II evidence).…”

Drug interaction between oral solution itraconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplantation recipients: an association with bioavailability of oral solution itraconazole

“…However, the achievement rate of optimal level could be higher than this rate because the previous reports applied a peak level measured 2 h after administration, while a trough level was applied in the present study [23]. There have been only limited data on the bioavailability of oral solution itraconazole after HSCT, particularly allogeneic HSCT [26,27]. Despite an interindividual variability, our results suggest that oral solution itraconazole (200 mg/day) could be useful in the prophylaxis or treatment of IFD after allogeneic HSCT.…”

Sirolimus-Itraconazole Interaction in a Hematopoietic Stem Cell Transplant Recipient

“…4 Itraconazole, a second-generation azole antifungal that is available in intravenous formulations and in a more bioavailable oral solution, is used to prevent fungal infections in HSCT recipients. [5][6][7] Its interactions with calcineurin inhibitors are well documented in the renal allograft setting. [8][9][10] In patients with HSCT, itraconazole has been found to interact with high-dose chemotherapeutic agents, leading to a survival disadvantage owing to enhanced myeloablative chemotherapy-induced organ toxicity.…”