Antifungal Prophylaxis with Posaconazole in Allogeneic Hematopoietic Stem Cell Transplantation Using Sirolimus for Prevention of Graft-Versus-Host Disease
Authors: Greco Raffaella , Barbanti Maria Chiara , Forcina Alessandra , Lupo Stanghellini Maria Teresa , Giglio Fabio , Morelli Mara , Vago Luca , Piemontese Simona , Messina Carlo , Sala Elisa , Pavesi Francesca , Marktel Sarah , Carrabba Matteo G , Assanelli Andrea , Bernardi Massimo , Peccatori Jacopo , Corti Consuelo , Ciceri Fabio 
Published: October 2019

Abstract
Invasive fungal infections (IFI) have emerged as a leading cause of morbidity and infection-related mortality among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients over the past two decades. Several new drugs have recently been introduced as antifungal prophylaxis, supported by results of prospective randomized trials. In agreement with the international guidelines, a mold-active antifungal prophylaxis is strongly recommended in high-risk patients receiving allo-HSCT, considering efficacy, different pharmacokinetic, drug-drug interactions, and toxicity profile of the various antifungal drugs.
Posaconazole, a triazole with broad-spectrum antifungal activity and a favorable toxicity profile, is the drug of choice for patients with graft versus host disease (GVHD). Consequently, posaconazole prophylaxis in allo-HSCT recipients is administered in combination with immunosuppressive drugs for GVHD prophylaxis and/or treatment, most commonly cyclosporine (CsA) or tacrolimus.
Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), largely used for GVHD prevention and treatment, but extensively metabolized by CYP3A4. As posaconazole strongly inhibits CYP3A4 its coadministration with sirolimus is contraindicated by the manufacturer of posaconazole, and up to now poorly described in literature.
In the San Raffaele Haematology and Bone Marrow Transplantation Unit, from 2010 to 2015, we retrospectively identified sixty-six patients that received posaconazole oral suspension as primary (n=43) or secondary (n=23) antifungal prophylaxis after allo-HSCT.
The majority of patients were affected by acute leukaemia (67%), not in remission at time of allo-HSCT (55%), and with a previous allo-HSCT reported for 50% of them, carrying an high risk for developing a post-transplant IFI. Median follow up was 357 days (range 43-1884) after HSCT. Posaconazole administration was given for a median of 221 days (range 13-966).
Thirty-two patients (49%) received posaconazole during engraftment phase, while 28 (42%) and 19 (29%) patients for IFI prophylaxis in the setting of acute or chronic GvHD respectively.
A concomitant administration of sirolimus was performed in 49 patients (74%). Sirolimus concentrations were monitored two times a week, while posaconazole was controlled in patients' serum on a weekly basis, during the first two months of treatment.
We observed a 55-70% steady-state dose reduction of sirolimus in 19 patients, after posaconazole introduction. Alternatively, patients with ongoing posaconazole prophylaxis received an initial empiric sirolimus dose reduction at 1 mg/day.
The co-administration of posaconazole and sirolimus resulted safe. Discontinuation was reported mainly in patients with documented IFI, who required a change of the antifungal drug. No adverse events potentially associated with sirolimus overexposure (i.e. sinusoidal obstructive syndrome, sirolimus-related thrombotic microangiopathy) were reported, although one-third of the patients experienced a transient and moderate elevation of sirolimus serum levels in the first week of coadministration.
In this analysis post-transplant IFI occurred in 14 cases. The risk of developing IFI was influenced by type of prophylaxis, resulting in 12% and 39% of IFI during primary and secondary prophylaxis respectively (p value 0.013; OR 4.89, CI 1.39-17.11). However the most significant and strong association was reported in concomitant with insufficient posaconazole serum levels (<0.5 ml/L), a known reported limitation of the oral solution formulation especially in patients with intestinal GVHD and/or diarrhea (p value <0,0001; OR 35.14, CI 6.43-192).
In patients with adequate posaconazole serum levels (>0.5 ml/L) the incidence of IFI was 5%, supporting the utility of therapeutic drug monitoring (TDM) in such conditions and generating interest for the use of the upcoming posaconazole tablets with improved bioavailability in allo-HSCT recipients.
In our experience concurrent sirolimus and posaconazole use was well tolerated, with a 55% to 70% sirolimus dose reduction at posaconazole initiation and close monitoring of serum sirolimus and posaconazole trough levels in the first months of co-administration.

Disclosures
No relevant conflicts of interest to declare.