Dual BCL-xL en BCL-2 remming toont activiteit bij hoog-risico myeloide maligniteiten

BACKGROUND: 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 anti-apoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. PATIENTS AND METHODS: We conducted a Phase 1 study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with 1) secondary (s-AML) or therapy-related AML, 2) accelerated- or blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or 4) relapsed/refractory (R/R) MDS with excess blasts. 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 2 dose was decitabine 20mg/m2 days 1-5, venetoclax 400mg/day days 1-14, and navitoclax 50mg/day days 1-14 for AP-MF, MDS/MPN, and R/R MDS. 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. CONCLUSION: Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.