Isavuconazole (ISAV) As Primary Anti-Fungal Prophylaxis in Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-Label, Prospective Study
Authors: Bose Prithviraj , McCue David , Wiederhold Nathan P. , Kadia Tapan M. , Borthakur Gautam , Ravandi Farhad , Yilmaz Musa , Takahashi Koichi , Thompson Philip A. , Pemmaraju Naveen , Daver Naval G. , Burger Jan A. , Cortes Jorge E. , Garcia-Manero Guillermo , Verstovsek Srdan , Konopleva Marina Y. , Jain Nitin , DiNardo Courtney D. , Alvarado Yesid , Naqvi Kiran , Kornblau Steven M. , Ferrajoli Alessandra , Wierda William G. , Estrov Zeev E. , Benton Christopher B. , Masarova Lucia , Montalban-Bravo Guillermo , Sasaki Koji , Rausch Caitlin R. , Marx Kayleigh , Qiao Wei , Huang Xuelin , Bivins Carol A. , Pierce Sherry A. , Kantarjian Hagop M. , Kontoyiannis Dimitrios P. 
Published: October 2019

Abstract
Introduction: 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.

Disclosures
Bose: CTI BioPharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding. Wiederhold:Astellas Pharmaceuticals: Research Funding. Kadia:Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Jazz: Consultancy, Research Funding. Ravandi:Abbvie: Research Funding; Xencor: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria. Thompson:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding; cellectis: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Daver:Sunesis: Consultancy; Otsuka: Consultancy; Incyte: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; ARIAD: Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Pfizer: Research Funding; Sunesis: Research Funding; ImmunoGen: Consultancy; Novartis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Pfizer: Consultancy. Cortes:Arog: Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Jain:Verastem: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Celgene: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologioes: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Cellectis: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Adaptive Biotechnologioes: Research Funding; Infinity: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Abbvie: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Kontoyiannis:Astellas Pharmaceuticals: Research Funding.