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ntroduction: Invasive fungal infections (IFIs) are important causes of morbidity and mortality among patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), and consensus guidelines recommend the use of mold-active antifungal prophylaxis (ppx), e.g., voriconazole (vori) or posaconazole (posa). Isavuconazole (ISAV), the most recently introduced triazole antifungal, is currently approved for the treatment of invasive aspergillosis and invasive mucormycosis. ISAV is an appealing option for ppx against IFIs in neutropenic pts with AML/MDS because of its extended spectrum, superior tolerability (over vori), fewer drug-drug interactions (than posa), absence of need for therapeutic drug monitoring (TDM) and lack of prolongation of the QT interval (enabling easier administration in pts receiving certain anti-leukemic targeted therapies, 5-HT3 antagonists, quinolones, etc). NCT03019939 is an investigator-initiated, phase 2, single-arm, open-label trial of primary antifungal ppx with ISAV in pts with AML/MDS.
Methods: Previously untreated adult pts with AML or MDS who are or are anticipated to become neutropenic as a result of their first therapy for AML/MDS are eligible to participate in this ongoing trial. Accrual of 100 pts is planned. Stopping rules exist for both futility and toxicity, assuming equivalence between ISAV and the current standard of care, posa, in preventing breakthrough IFIs (expected rate, 5%). In pts who have begun definitive anti-leukemic treatment, ISAV must be initiated within 4 days. Use of systemic antifungal therapy for >72 hours during the week prior to ISAV initiation is not allowed. ISAV is administered orally as the pro-drug, isavuconazonium sulfate, and dosed per the US label. ISAV ppx is administered until recovery from neutropenia (absolute neutrophil count (ANC) ≥0.5 x 109/L and attainment of complete remission (CR), with or without complete count recovery, occurrence of a proven or probable IFI (per 2008 EORTC/MSG criteria), development of unacceptable toxicity, pt withdrawal or death, or for a maximum of 12 weeks. The primary endpoint is the incidence of proven/probable IFI during the study period (up to 30 days from the last dose of ISAV). ISAV plasma concentrations are determined immediately pre-dose on days 8 and 15 using a validated assay.
Results: A total of 50 pts were enrolled between April 28, 2017 and July 10, 2018. Four pts did not begin ppx with ISAV (1 each could not complete caspofungin washout and screening tests in time, 2 insurance denials). Of the remaining 46 pts (Table 1), 2 remain on study. Reasons for going off study (n = 44) included achievement of CR with neutrophil recovery (n = 26), completion of 12 weeks of therapy (n = 7), possible IFI (n = 5), investigator decision (n = 2), death (n = 2, 1 disease progression, 1 cardiac arrest), probable IFI (n = 1) and transaminitis (n = 1). In these 44 pts, the median duration of ISAV ppx was 30 (10-86) days. Only 1 case of proven breakthrough IFI occurred: a gluteal abscess that later grew Candida glabrata in a pt who had come off study upon achievement of CR. One case of probable IFI (focal mass-like opacity with ground-glass halo on CT; elevated Aspergillus antigen in broncho-alveolar lavage (BAL) fluid) occurred. All 5 cases of possible IFI were based on pulmonary radiologic findings alone: lower respiratory fungal cultures remained negative at 4 weeks in all 5 pts, and galactomannan was not detected in serum or BAL fluid in any pt. Tolerability of ISAV was excellent, with mild transaminitis attributed to ISAV reported in 1 pt (2%). No pt experienced QTc prolongation while on ISAV. Plasma ISAV levels were measured in 62 blood samples from 34 individual pts, including 28 paired samples. Median (range) ISAV concentrations were 3.74 (2.03-7.65) and 4.1 (2.17-9.25) mcg/ml on days 8 and 15, respectively. There was no correlation between plasma ISAV concentrations (available in 4 of the 7 pts) and the occurrence of confirmed, probable or possible IFI.
Conclusions: These results demonstrate ISAV to be a safe and effective alternative for antifungal ppx in treatment-naïve pts with AML/MDS undergoing induction therapy with a variety of different regimens. ISAV's weak inhibition of P-glycoprotein and lack of risk of QT prolongation may make ISAV particularly attractive for antifungal ppx in the era of recently approved or emerging AML therapies such as enasidenib, ivosidenib, midostaurin and quizartinib.
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