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Transcriptional activity of a T-ALL PDX line following in vitro treatment with idasanutlin, navitoclax (ABT-263), or combination therapy

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with an umet need for improved therapies. We explored the potentially synergic combination of MDM2 inhibition and Bcl-2, Bcl-xL inhibition through cotreatment of T-ALL models with idasanutlin and navitoclax. In order to understand the early transcriptional changes induced by this combination therapy, we performed RNA sequencing on drug treated cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240444 | GEO | 2023/10/16

REPOSITORIES: GEO

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Transcriptional activity of a T-ALL PDX line following in vitro treatment with idasanutlin, navitoclax (ABT-263), or combination therapy

Project description:Transcriptional activity of a T-ALL PDX line following in vitro treatment with idasanutlin, navitoclax (ABT-263), or combination therapy

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Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine

Project description:Background: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective against most acute myeloid leukemia (AML) subtypes, but less so against other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate BH3-only 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 of dose-escalated navitoclax added to venetoclax/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. Dose-escalation for BP-MF and s-AML was not completed due to discontinued navitoclax supply. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (47%). 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 20 mg/m2 days 1-5, venetoclax 400 mg/day days 1-14, and navitoclax 50 mg/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 aberrant monocytes in subjects with monocytic disease, and higher baseline myeloblast dependence on BCL-2 and BCL-xL as predictive of response. Conclusion:Navitoclax added to venetoclax/decitabine is safely tolerable and is active in patients with high-risk myeloid malignancies.

2026-04-20 | GSE312447 | GEO