Isavuconazole as Primary Anti-Fungal Prophylaxis in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-Label, Prospective, Phase II Study.

BACKGROUND Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed 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 less significant drug-drug interactions compared with other triazoles. METHODS In our investigator-initiated, phase 2 trial (NCT03019939), treatment-naïve adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (ANC ≥ 0.5x109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI, EORTC/MSG criteria), 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 out of 75 enrolled patients received ISAV PAP (median age: 67 years, median ANC at enrollment: 0.72x109/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 on days 8 and 15 were consistently above 1 µg/mL, showed low intra-individual variation, and were not significantly influenced by the patients' chemotherapy regimen. Tolerability of ISAV was excellent, with only three 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 anti-leukemia therapies.