Jian-Qing Mi | PubMed Health

PubMed2026

Timing matters: Impact of covalent BTK inhibitor dose modifications on outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia-A 7-year real-world study.

BACKGROUND: Covalent BTK inhibitors (cBTKis) are the cornerstone of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) therapy, yet real-world data on dose modifications and their differential impact on long-term outcomes remain incompletely defined. This study investigated the incidence, timing, and the effectiveness of drug switching in a real-world CLL cohort. METHODS: In this 7-year retrospective real-world study, 324 CLL/SLL patients treated at a specialized Shanghai outpatient clinic (April 2018-April 2025; median follow-up, 42 months) were analyzed. Dose modifications were classified as dose interruption (DI) or dose reduction (DR). Their prognostic impact on progression-free (PFS) and overall survival (OS) was assessed by Kaplan-Meier analysis and multivariate Cox regression. RESULTS: The 42-month PFS rate was 70.2%. Of 324 patients, 229 (70.7%) experienced dose reductions or interruptions; infections were the predominant cause (61.9%). The full-dose (FD) group (n = 90) demonstrated superior 4-year PFS (93% vs. 58%, p < .001) and OS (98% vs. 76%, p = .007). Early modifications (0-3 months) were independent predictors of inferior PFS (hazard ratio [HR], 3.93, p = .008) and OS (HR, 3.29, p = .014). Prolonged DI (>14 days) was associated with inferior PFS (HR, 2.64) and OS (HR, 2.15), whereas DR and short DI (≤14 days) had negligible impact. Early (0-3 months) prolonged DI was devastating (3-year PFS, 41.2%; HR, 3.84, p < .001). cBTKi switching (n = 82; 100% nonprogression-driven) shortened DI (median, 6 vs. 14 days) and was independently associated with superior OS (HR, 0.34, p = .018) and PFS (HR, 0.36, p = .022). CONCLUSIONS: Early prolonged DI is the dominant adverse prognostic factor in cBTKi-treated CLL/SLL. Proactive switching minimizes treatment gaps and improves survival, supporting a timing-aware, DI- versus DR-informed approach to dose management.

Humans↗

PubMed2025

Mitochondrial dysfunction fuels drug resistance in adult T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a relatively rare hematological malignancy, characterized by the uncontrolled proliferation of immature T lymphoblasts and associated with a generally unfavorable prognosis. Our previous research has demonstrated that decreased mitochondrial activity is associated with the aggressiveness of T-ALL tumors. However, the mechanisms underlying this phenomenon and its contribution to treatment resistance remain largely elusive. METHODS: We have built up the largest known T-ALL tumor bank, with a median follow-up of 32 months, including our transcriptomic data from 79 newly sequenced tumors that adds to the 54 publicly accessible samples. Computational analyses and a series of functional assays were performed to investigate the molecular links between altered mitochondrial activity and drug resistance. RESULTS: The transcriptomic analysis revealed that down-regulation of mitochondrial activity is a potent driver of ABCB1 activation, a gene strongly associated with multidrug resistance. In tumors with low mitochondrial activity, the impaired fatty acids β-oxidation leads to intracellular lipid accumulation, which is directly involved in ABCB1 activation. Indeed, our data show that lipid neo-synthesis and accumulation promotes the activation of lipogenic transcription factors, liver X receptors (LXRs), which act as drivers of ABCB1 expression. Tumor data analyses confirmed that high ABCB1 expression in tumour samples is indeed associated with reduced mitochondrial gene expression, lipid droplet enrichment, increased tumour aggressiveness, and significantly shorter patient survival. CONCLUSIONS: Our study demonstrates that reduced mitochondrial activity drives multidrug resistance in adult T-ALL via lipid-mediated activation of ABCB1. These findings enhance our understanding of the biology of aggressive T-ALL and provide insight into mechanisms of resistance to conventional chemotherapy. Consequently, we propose that targeting de novo lipogenesis and restricting dietary fats, such as caprylic acid, may help overcome treatment resistance in patients with T-ALL exhibiting low mitochondrial activity. TRIAL REGISTRATION: The clinical trial was registered under the identifiers ChiCTR-ONRC-14004968 and ChiCTR2000031553 at ClinicalTrials.gov.

Adult↗