Phase I study of alvocidib followed by 7+3 (cytarabine + daunorubicin) in newly diagnosed acute myeloid leukemia

Purpose: Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7þ3 induction therapy. Patients and Methods: A multiinstitutional phase I dose-escalation study of alvocidib on days 1–3 followed by 7þ3 (cytarabine 100 mg/m²/day i.v. infusion days 5–12 and daunorubicin 60 mg/m² i.v. days 5–7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded. Results: There was no MTD on this study; the recommended phase II dose of alvocidib was 30 mg/m² i.v. over 30 minutes followed by 60 mg/m² i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome–related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively). Conclusions: Alvocidib can be safely administered prior to 7þ3 induction with encouraging clinical activity. These findings warrant further investigation of alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984.