Overexpression of anti-apoptotic protein BCL-2 and hypermethylation are hallmarks of acute lymphoblastic leukemia (ALL) and can be pharmacologically addressed by venetoclax (VEN) and hypomethylating agents (HMA) such as azacytidine (AZA) or decitabine (DEC). AZA-induced metabolic suppression as well as overall anti-leukemic activity alone and in combination with VEN was generally weaker compared to DEC. Altogether, we herein demonstrate that combined VEN and HMA application acts synergistically and significantly reduces the leukemic burden in ALL cell lines via impairment of tumor cell metabolism and mitochondrial function.

This optimized model demonstrated significant improvement, reducing the difference in the description of exposure for the microdose study from 5- to 1-fold, without compromising the description at therapeutic doses. This modified model has a wider range of applicability across doses and could support the extrapolation of microdose study results to therapeutic doses in future research.

P1, N=18, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P2/3, N=450, Enrolling by invitation, First Affiliated Hospital of Zhejiang University

P3, N=466, Recruiting, Alliance for Clinical Trials in Oncology | Not yet recruiting --> Recruiting | Initiation date: Jan 2026 --> Apr 2026

P2/3, N=267, Enrolling by invitation, First Affiliated Hospital of Zhejiang University

P1, N=12, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2026 --> May 2027 | Trial primary completion date: May 2026 --> May 2027

P2, N=120, Recruiting, Chinese PLA General Hospital | Trial primary completion date: Dec 2027 --> Sep 2027

pFAO blockade synergizes with chemotherapy drugs such as venetoclax and cytarabine, enabling exploitation of metabolic vulnerabilities to improve therapeutic outcomes. Integrating solid tumor and leukemia insights, peroxisomes emerge as dynamic lipid-processing organelles coupling FAO, redox buffering, and inter-organelle exchange to cancer persistence. Targeting peroxisome-mediated lipid delivery offers a frontier for overcoming metabolic resilience and therapeutic resistance in leukemia.

Azacitidine was administered after dialysis sessions, while venetoclax dosing was adjusted because of concomitant posaconazole prophylaxis. Approximately one year after diagnosis, relapsed AML was identified on peripheral blood flow cytometry. This case highlights the feasibility of venetoclax-based lower-intensity therapy in selected dialysis-dependent AML patients while underscoring the persistent therapeutic limitations and adverse prognosis associated with relapsed disease in this population.

In this cohort, BRAF-mutant AML patients had poor overall survival with currently available treatments, including venetoclax-based regimens. Drug sensitivity data suggest possible avenues for targeted treatment of BRAF-mutated AML.

Based on treatment regimens, the patients were categorized into chemotherapy group ("3+7"regimen), demethylation therapy (HMA) group (decitabine-based therapy), and UCB group (venetoclax combined with azacitidine plus UCB reinfusion). Cytokine level analysis demonstrated that the direct co-culture group showed higher levels of TNF-α and IFN-γ, as well as lower levels of IL-6 compared to the control group (P<0.001). Immunocytes such as NK cells in UCB may promote immune function reconstruction and hematopoietic recovery in patients, thereby improving their prognosis.