Navitoclax Plus Venetoclax and Decitabine Shows Early Activity in High-Risk Myeloid Malignancies

Clinical Summary:

• Design/Population: This phase 1 study evaluated navitoclax plus venetoclax and decitabine in patients with high-risk myeloid malignancies. 
• Key Outcomes: The triplet regimen demonstrated manageable safety and encouraging preliminary activity, with an overall response rate of 60%. Correlative studies suggested dual BCL-2/BCL-xL dependence may predict response.
• Clinical Relevance: These findings support further evaluation of navitoclax in combination with venetoclax and decitabine for patients with high-risk myeloid malignancies.

Results from a phase 1 study demonstrated that the addition of navitoclax, a BCL-2/BCL-xL inhibitor, to venetoclax plus decitabine was safe and showed encouraging preliminary activity among patients with high-risk myeloid malignancies. 

“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,” stated Evan Chen, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and coauthors. “One resistance mechanism to BCL-2 inhibition is increased dependence on alternate antiapoptotic proteins, such as BCL-xL.” 

In this study, researchers enrolled 16 patients with either secondary or therapy-related AML, accelerated- or blast-phase myelofibrosis, overlapping and excess blast myelodysplastic syndromes or myeloproliferative neoplasms, or relapsed or refractory excess blast myelodysplastic syndromes or myeloproliferative neoplasms. 

Patients received either 25 or 50 mg of navitoclax (on days 3 through 14 during cycle 1 and on days 1 through 14 of subsequent cycles) plus 400 mg of once daily venetoclax (for 14 or 21 days depending on disease subtype) and 20 mg/m² of decitabine (on days 1 to 5) in 28 day cycles. Primary end points included objective response rate (ORR), safety, and recommended phase 2 dose. 

At analysis, the overall ORR was 60%. The most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). One dose-limiting toxicity of delayed neutrophil recovery was reported, and no clinically significant bleeding events were reported. 

The recommended phase 2 dose was identified as of 20 mg/m² of decitabine (on days 1 through 5) plus 400 mg of venetoclax (on days 1 through 14) and 50 mg of navitoclax (on days 1 to 14) for patients with accelerated-phase myelofibrosis, overlapping myelodysplastic syndromes or myeloproliferative neoplasms, and relapsed or refractory myelodysplastic syndromes. 

Correlative analyses demonstrated preservation of immature platelet fractions despite reductions in mature platelets, decreased disease-associated monocytes among patients with monocytic disease, and greater dependence of myeloblasts on BCL-2 and BCL-xL in responding myeloblasts. 

“Navitoclax added to venetoclax and decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies,” concluded Dr Chen et al. 

Source:

Chen EC, Liu Y, Bell HL, et al. Dual BCL-xL and BCL-2 inhibition for advanced myeloid neoplasms: A phase I dose-escalation study of navitoclax, venetoclax, and decitabine. Clin Cancer Res. Published online: June 25, 2026. doi:10.1158/1078-0432.ccr-25-4905