Exposure-Response and Prognostic Analysis of Venetoclax Therapeutic Drug Monitoring in Newly Diagnosed AML
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Complete remission rate
研究概览
简要总结
Venetoclax combined with azacitidine (VEN-AZA) is the current first-line standard of care for newly diagnosed acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Although this regimen substantially improves remission rates, marked inter-individual variability is observed in clinical practice-ranging from severe myelosuppression or tumor lysis syndrome in some patients to poor response or early relapse in others. Venetoclax is primarily metabolized by CYP3A4, and its systemic exposure is modulated by multiple factors, including hepatic and renal function, concomitant medications (particularly azole antifungals), and UGT1A1 polymorphisms, leading to a 50%-70% inter-individual variability in blood drug concentrations.
Despite this variability, the current VEN-AZA regimen employs a fixed-dose strategy (400 mg/day) without incorporating therapeutic drug monitoring (TDM) to guide individual dosing. Critical knowledge gaps remain: (1) whether a clear exposure-response relationship exists between venetoclax exposure and composite remission rate (CR+CRi); (2) what blood concentration range optimizes efficacy while minimizing toxicity; (3) which covariates significantly influence venetoclax clearance; and (4) whether early concentration sampling can reliably predict subsequent exposure and clinical outcomes.*
To address these questions, investigators designed a prospective study enrolling newly diagnosed AML patients receiving VEN-AZA therapy. Investigators aim to systematically characterize the exposure-response relationship, establish an optimal therapeutic concentration window, identify key covariates contributing to inter-individual pharmacokinetic variability, and evaluate early-sampling prediction strategies. The findings are expected to provide direct evidence for TDM-guided individualized dosing and to support a paradigm shift from a "fixed-dose" to a "concentration-guided" approach in precision AML therapy.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis: Newly diagnosed acute myeloid leukemia (AML) confirmed according to the WHO 2022 or International Consensus Classification (ICC) criteria, based on bone marrow morphology, flow cytometry, and molecular genetics. Acute promyelocytic leukemia (APL) is excluded.
- •Treatment regimen: Planned or already initiated first-line therapy with venetoclax plus azacitidine (VEN-AZA), with dosing determined by the treating physician according to routine clinical practice (no protocol-mandated dose restrictions).
- •Age: ≥ 16 years.
- •Informed consent: Willingness and ability to provide written informed consent for participation in this observational study.
- •Follow-up: Agreement to attend scheduled follow-up visits and to permit clinical data collection at the time points specified in the study protocol.
排除标准
- •Prior AML therapy: Prior treatment for AML, with the exception of leukapheresis, hydroxyurea, low-dose cytarabine, or corticosteroids.
- •Concurrent interventional trials: Current participation in any interventional clinical trial, including those involving investigational agents.
- •Extremely short life expectancy: Judged by the investigator to be unable to complete at least one full cycle of therapy and the associated follow-up.
研究组 & 干预措施
Venetoclax combined with Azacitidine
ND-AML patients received the venetoclax plus azacitidine as induction. Dosage is determined by clinicians based on routine practice (not mandatory in the study protocol). Venetoclax concentration data were collected on days 8, 15, and 22, and the steady-state trough concentration (Cmin), peak concentration (Cmax), and area under the curve (AUC) were calculated.
结局指标
主要结局
Complete remission rate
时间窗: At the end of induction treatment (28 days ± 7days)
Percentage of subjects with complete remission (CR) and incomplete hematologic recovery (CRi)
次要结局
- Hematological toxicity(Start of treatment to 2 weeks after end of treatment)
- Non-hematological toxicity(Start of treatment to 2 weeks after end of treatment)
- Overall Survival(24 months)
- Event-free Survival(24 months)
- Measurable residual disease response rate(At the end of induction treatment (28 days ± 7days))
研究者
CHEN Jia
Chief Physician of Hematology. Clinical Professor. Principal Investigator
The First Affiliated Hospital of Soochow University