TY - JOUR
T1 - Isavuconazole as Primary Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome
T2 - An Open-label, Prospective, Phase 2 Study
AU - Bose, Prithviraj
AU - McCue, David
AU - Wurster, Sebastian
AU - Wiederhold, Nathan P.
AU - Konopleva, Marina
AU - Kadia, Tapan M.
AU - Borthakur, Gautam
AU - Ravandi, Farhad
AU - Masarova, Lucia
AU - Takahashi, Koichi
AU - Estrov, Zeev
AU - Yilmaz, Musa
AU - Daver, Naval
AU - Pemmaraju, Naveen
AU - Naqvi, Kiran
AU - Rausch, Caitlin R.
AU - Marx, Kayleigh R.
AU - Qiao, Wei
AU - Huang, Xuelin
AU - Bivins, Carol A.
AU - Pierce, Sherry A.
AU - Kantarjian, Hagop M.
AU - Kontoyiannis, Dimitrios P.
N1 - Funding Information:
Financial support. Astellas Pharma Global Development provided the study drug and funding for this investigator-initiated trial (to D. P. K.). D. P. K. acknowledges the Texas 4000 Distinguished Professorship for Cancer Research and the National Institutes of Health/National Cancer Institute Cancer Center CORE Support grant (number 16672).
Funding Information:
Potential conflicts of interest. P. B. has received grants (research support) and personal fees from Incyte, Celgene, CTI Biopharma, Kartos Therapeutics, and BluePrint Medicines, and grants from Astellas, Constellation Pharmaceuticals, NS Pharma, Promedior, and Pfizer. N. P. W. has received grants from Astellas Pharma, bioMérieux, Cidara, Covance, F2G, and Viamet; has served on the advisory board of Mayne Pharma; and has served on the speaker’s bureau for Gilead. T. M. K. has received grants and personal fees from Pfizer, AbbVie, Genetech, and Jazz Pharma, as well as grants from BMS and Celgene; and has served as a consultant for Novartis and Agios. N. P. has received research funding from Samus, Cellectis, Plexxikon, and Daiichi-Sankyo; has received grants from the Sager Strong Foundation and Affymetrix; has received research support and personal fees from AbbVie, Stemline, and Novartis; has received personal fees from the Blueprint Medicines Corporation, Celgene, Incyte, MustangBio, Roche Diagnostics, and FLB; has served on the Board of Directors of Dan’s House of Hope; and has been a Board Member of HemOnc Times/Oncology Times. H. M. K. has received grants and honoraria from AbbVie, Agios, Amgen, Cyclacel, Immunogen, and Pfizer; grants from Ariad, Astex, BMS, Daiichi-Sankyo, Jazz Pharma, and Novartis; and honoraria from Takeda; and has also served on the advisory board of Actinium. D. P. K. has received research support from Astellas Pharma, Merck, Pfizer, and T2 Biosystems; has received honoraria for lectures from Merck & Co, Gilead, F2G Inc, Pfizer, and United Medical; has served as a consultant for Astellas Pharma, Cidara, Amplyx, Astellas, Pulmocide, and Mayne Pharma; and has served on the advisory board of Merck & Co. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Publisher Copyright:
© 2020
PY - 2021/5/15
Y1 - 2021/5/15
N2 - Background: Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug-drug interactions compared with other triazoles. Methods: In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose. Results: Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations. Conclusions: ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies. Clinical Trials Registration: NCT03019939.
AB - Background: Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug-drug interactions compared with other triazoles. Methods: In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose. Results: Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations. Conclusions: ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies. Clinical Trials Registration: NCT03019939.
KW - Antifungal prophylaxis
KW - Chemotherapy
KW - Invasive fungal infection
KW - Isavuconazole
KW - Leukemia
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U2 - 10.1093/cid/ciaa358
DO - 10.1093/cid/ciaa358
M3 - Article
C2 - 32236406
AN - SCOPUS:85092169897
SN - 1058-4838
VL - 72
SP - 1755
EP - 1763
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 10
ER -