Isavuconazole as Primary Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-label, Prospective, Phase 2 Study

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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 &amp;gt; 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trials Registration</jats:title> <jats:p>NCT03019939.</jats:p> </jats:sec>

Therapeutic Drug Monitoring of Isavuconazole: Serum Concentration Variability and Success Rates for Reaching Target in Comparison with Voriconazole

“…The clinical phase III trial SECURE found the majority of s-ISZ measurements were within the range of 1–7 mg/L [ 23 ]. The median value in the present study was 4.3 mg/L and well within that range, the same as in other studies [ 7 , 8 , 9 , 12 , 17 , 24 , 25 , 26 ]. In the present study, the majority of the s-ISZ measurements were also within the recommended range, but for VRZ a third of TDM measurements were outside the recommended range, which is also in accordance with the literature [ 27 ].…”

“…Two patients had breakthrough fungal infections even with high levels of s-ISZ. Breakthrough fungal infections during ISZ prophylaxis or treatment have also been reported by others [ 7 , 8 , 9 , 10 , 11 , 32 , 33 ]. Breakthrough fungal infections during ISZ prophylaxis in hematological patients when s-ISZ was within the therapeutic range have also been observed [ 9 ].…”

“…On the contrary, ISZ did not show non-inferiority to caspofungin in the treatment of candidaemia and candidiasis [ 6 ]. In addition to treatment, ISZ was found to be safe as prophylaxis in a clinical trial with acute myeloid leukemia and myelodysplastic syndrome patients of which almost half received targeted treatments such as venetoclax and FLT3 inhibitors [ 7 ]. Isavuconazole as prophylaxis has also been reported in other studies [ 8 , 9 , 10 , 11 ] as well as the use of ISZ in children [ 12 ] and patients with chronic pulmonary aspergillosis (CPA) [ 13 , 14 ].…”

Venetoclax combination therapy with hypomethylating agents in young adults with relapsed/refractory acute myeloid leukaemia

“…At the moment, we routinely use posaconazole as antifungal prophylaxis, even when isavuconazole is usually better tolerated and has fewer interactions than other azoles. 43 Isavuconazole, however, may also worsen myelosuppression due to increased levels of VEN, despite being a moderate CYP3A4 inhibitor. So far, there is no evidence that the use of isavuconazole is preferable to posaconazole concomitantly with VEN.…”

Isavuconazole—Animal Data and Clinical Data

“…Of 20 patients enrolled, 2 (10%) were considered as failure as they developed a possible fungal infection. A more recent open-label phase II study in AML and myelodysplastic syndrome (MDS) patients undergoing remission-induction therapy reported the development of b-IFD (2 probable-pulmonary aspergillosis-and 8 possible) in 10 (15%) of 75 enrolled patients while on ISV prophylaxis [24]. The possible explanations of these figures may be the advanced age of the population (median: 67 years) and the prolonged neutropenia, due to intensive chemotherapy or to venetoclax-based regimens.…”