Venetoclax TDM in Newly Diagnosed AML: Exposure-Response and Prognosis

Exposure-Response and Prognostic Analysis of Venetoclax Therapeutic Drug Monitoring in Newly Diagnosed AML

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.

Inclusion Criteria:

1. 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.
2. 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).
3. Age: ≥ 16 years.
4. Informed consent: Willingness and ability to provide written informed consent for participation in this observational study.
5. Follow-up: Agreement to attend scheduled follow-up visits and to permit clinical data collection at the time points specified in the study protocol.

Exclusion Criteria:

1. Prior AML therapy: Prior treatment for AML, with the exception of leukapheresis, hydroxyurea, low-dose cytarabine, or corticosteroids.
2. Concurrent interventional trials: Current participation in any interventional clinical trial, including those involving investigational agents.
3. 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.