Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A Phase I Dose-Escalation Study of Navitoclax, Venetoclax, and Decitabine.
Клиническое исследование I фазыСтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Chen Evan C, Liu Yiwen, Bell Hayden L, Ryan Jeremy, Wu Jason, Minihane Emma-Jayne, Luskin Marlise R, Winer Eric S, Vedula Rahul, Volpe Virginia, Stahl Maximilian, Roberts Daniel, Galinsky Ilene, Gerard Mary, Hersch Matthew, Lee Jessica, Neuberg Donna, Stone Richard M, DeAngelo Daniel J, Letai Anthony, Lane Andrew A, Garcia Jacqueline S
Аннотация
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.
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.