{"database":"GEO","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"," Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312447"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine","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.","dates":{"publication":"2026/04/20"},"accession":"GSE312447","cross_references":{"GSM":["GSM9346071","GSM9346070","GSM9346073","GSM9346072","GSM9346064","GSM9346074","GSM9346063","GSM9346066","GSM9346065","GSM9346068","GSM9346067","GSM9346069"],"GPL":["24676"],"GSE":["312447"],"taxon":["Homo sapiens"]}}