Isavuconazole Therapy of Disseminated and Encephalic Saprochaete Capitata Infection in an Acute Myeloid Leukemia Patient Treated with Midostaurin
1 Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.
2 Department of Public Health and Infectious Diseases, Sapienza University, S.M. Goretti Hospital, Latina, Italy.
3 Hematology, Dipartimento Medicina Traslazionale e di Precisione, AOU Policlinico Umberto I, Sapienza University of Rome, Italy.
4 Department of Medical Oncology, Sapienza University of Rome, Medical and Surgical Sciences and Biotechnology, Rome, Italy.
Received: February 8, 2020
Accepted: April 5, 2020
Mediterr J Hematol Infect Dis 2020, 12(1): e2020026 DOI 10.4084/MJHID.2020.026
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Background: Saprochaete capitata is a rare and emerging opportunistic fungus, involving immunocompromised hosts, in particular, neutropenic patients after chemotherapy.
Case Report: We report a case of disseminated and cerebral infection by Saprochaete capitata,
in a 68-year-old woman affected by acute myeloid leukemia that was
successfully managed with liposomal amphotericin B and isavuconazole.
The patient successfully underwent two courses of consolidation with high doses of cytarabine and midostaurin while under isavuconazole therapy without any midostaurin related toxicity (the patient was monitored biweekly for QTc prolongation on each ambulatory visit). During maintenance with midostaurin, we performed a therapeutic drug monitoring (TDM) of isavuconazole 5.2 µg/ml (normal range 2-5 µg/ml), no adjustment was undertaken. Eight months later, AML is in complete remission, and fungal infection is improving on isavuconazole (Figure 2), despite the prolonged neutropenia induced by the consolidation cycles.
Indeed, our case raises the challenging question of the appropriateness of administering midostaurin concomitantly with a CYP3A4 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, being posaconazole and voriconazole potent inhibitors of CYP3A4. Furthermore, an increased risk of QTc prolongation should be considered when patients receive 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. 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.
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. Isavuconazole is not in-label for IFI prophylaxis, but retrospective studies[18,19] suggest it could be an interesting option to be investigated in settings similar to our case.
Interestingly, few data exist about isavuconazole penetration in cerebral tissue, and experiences are mediated from mice models. In a patient with AML and cerebral aspergillosis, isavuconazole concentrations measured in the inflammatory brain tissue surrounding the abscess were similar to plasma, while the concentration in the liquid of the abscess was quasi-null. Two other patients with cerebral aspergillosis were treated with isavuconazole and required surgery for the progression of the infection. Bioptic samples showed increased drug concentration in the abscess and inflamed meninges compared to unaffected brain tissue. Differently from these cases, the outcome of our patient was favorable. Similarly, isavuconazole was also utilized with success to treat Rhino-Orbital-Cerebral Mucormycosis.
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