Shrunken hypodensae cystic hepatic lesion of 11 mm. the risk of side effects including QTc prolongation,5 as per protocol, we decided not to give the standard posaconazole antifungal prophylaxis, and we planned a preemptive antifungal approach with weekly serum galactomannan monitoring and precocious chest Computed Tomography (CT) in case of persisting neutropenic fever. On day +8, she developed neutropenic fever, and empirical anti-bacterial treatment with piperacillin/tazobactam and teicoplanin was started. After 48 hours, she was still febrile; therefore, she underwent a CT scan that revealed a 20 mm lung nodule, with halo-sign. Considering a possible invasive fungal infection (IFI) (serum galactomannan assay was negative), we started liposomal amphotericin B (3 mg/kg/day). Two days later, she was still febrile, and blood cultures showed fungemia, galactomannan raised to 0.6 in two blood samples; therefore, liposomal amphotericin B dosage was increased to 5 mg/kg/day for 9 days, with defervescence within few days. Later, when neutropenia Dynarrestin recovered, the CT-scan showed the evolution of the lung nodule into a cavitary lesion (Figure 1A), multiple liver abscesses (Figure 1B), and a single brain abscess in the left head of the caudate nucleus (Figure 1CCD). We then decided to discharge the patient and to shift antifungal treatment from intravenous liposomal amphotericin B to oral isavuconazole. We chose oral isavuconazole instead of oral voriconazole, which is a standard therapy of infection6,7 because isavuconazole is a mild/moderate inhibitor while voriconazole is a potent inhibitor of CYP3A4.5 Isavuconazole was also chosen because of its in vitro activity against infection. A) In the left lung is present a 7 mm excavation scar (white arrow). B) CT scan of the abdomen. Shrunken hypodensae cystic hepatic lesion of 11 mm. C) Brain CT: A 9 mm cystic lesion surrounded by concentric rim is present in the left head of the caudate nucleus. Discussion This case illustrates that isavuconazole may be an option in the treatment of infections, and that may be a safe choice if a co-administration with midostaurin is required. A further case of safe isavuconazole and midostaurin therapy in an AML patient with a possible pulmonary fungal infection has been recently reported.12 Indeed, our case raises the challenging question of the appropriateness of administering midostaurin concomitantly with a CYP3A4 Dynarrestin inhibitor. Posaconazole and voriconazole are drugs of the first choice in the primary antifungal prophylaxis and therapy of invasive aspergillosis and other IFIs, respectively.13,14 However, in patients affected by FLT3 positive AML caution is requested when triazoles are administered concomitantly with midostaurin, given the possible toxicity related to the increased exposure to the FLT3 inhibitor, Nedd4l being posaconazole and voriconazole potent inhibitors of CYP3A4. Furthermore, an increased risk of QTc prolongation should be considered when patients receive Dynarrestin midostaurin in association with other drugs that can prolong QTc, as the above triazoles.4,5 This limitation in the prevention and treatment of IFIs in FLT3 positive AML patients represents a challenging issue in the clinical practice, considering that IFIs significantly affect complete remission achievement and long-term survival of AML patients Dynarrestin 15. Again, the protective effects of mold active antifungal prophylaxis during induction and salvage chemotherapy for AML may have long-lasting benefits that extend even after the allogeneic stem cell transplant procedure, which is indicated in FLT3 positive AML patients after the achievement of complete remission because of the high risk of leukemia relapse.16 On the other hand, the contraindication of the concomitant use of midostaurin and triazoles is controversial. Ouatas et al. analyzed data from the Ratify study focusing on the subset of patients with concomitant use of midostaurin and fluconazole, posaconazole, or voriconazole in prophylaxis.3,17 In that study, concomitant use of various CYP3A4 inhibitors and antifungals agents was permitted with caution but without any specific recommendation on how to perform dose adjustment. More than half of patients received posaconazole or voriconazole during induction, consolidation, or maintenance therapy. In those patients in which midostaurin plasma levels were measured, a 1.44-fold increase in midostaurin through levels was observed when the strong CYP3A4 inhibitors posaconazole or voriconazole were co-administered, and no increase of adverse events nor impact on efficacy outcomes were observed, therefore dose modification does not seem required.17.
