Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A Phase I Dose-Escalation Study of Navitoclax, Venetoclax, and Decitabine

Abstract Purpose: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate antiapoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. We conducted a phase I study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with advanced myeloid malignancies. Patients and Methods: Eligible patients had a diagnosis of (i) secondary or therapy-related AML, (ii) accelerated- or blast-phase myelofibrosis (AP/BP-MF), (iii) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or (iv) relapsed/refractory (R/R) MDS with excess blasts. In 28-day cycles, subjects received navitoclax doses of 25 or 50 mg/day given for days 3 to 14 during cycle 1 and days 1 to 14 in subsequent cycles, target venetoclax doses of 400 mg/day given for days 1 to 14 or days 1 to 21 depending on the myeloid malignancy subtype, and decitabine doses of 20 mg/m2/day given for days 1 to 5. Results: Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase II dose was decitabine 20 mg/m2 days 1 to 5, venetoclax 400 mg/day days 1 to 14, and navitoclax 50 mg/day days 1 to 14 for AP-MF, MDS/MPN, and R/R MDS, respectively. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects. Conclusions: Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.