Association between venetoclax concentration and febrile neutropenia in acute leukemia: a retrospective analysis

Venetoclax, a selective BCL-2 inhibitor, shows variable pharmacokinetics; the ABCB1 1236C>T (rs1128503) TT genotype is associated with a higher peak concentration.

Venetoclax, a selective BCL-2 inhibitor, is effective in acute leukemia but its pharmacokinetics are variable, justifying assessment of therapeutic drug monitoring. The authors retrospectively analysed 123 patients treated between August 2023 and March 2025, seeking determinants of plasma concentrations and their relationship with febrile neutropenia, then defining predictive thresholds using ROC curves. Febrile neutropenia occurred in 35 patients (28.5 %), with trough (C0) and peak (C6) concentrations significantly higher than in other patients (1519.55 versus 1400.32 ng/mL and 2834.50 versus 2337.74 ng/mL). Age, concomitant azoles and prior transplantation were determinants of C0, while the ABCB1 1236C>T (rs1128503) TT genotype predicted elevated C6; a C0 above 1202.07 ng/mL or a C0/D ratio above 6.85 ng/mL per mg was associated with significantly higher febrile neutropenia incidence. The authors propose concentration monitoring as a way to identify patients at increased risk.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This sits closer to therapeutic drug monitoring than to pharmacogenetics: the only genetic contribution is ABCB1 1236C>T on peak concentration, a marker that is neither actionable nor endorsed by CPIC. The determinants that matter are pharmacological and already known — age and above all azoles, CYP3A inhibitors — which reduces the problem to interaction management rather than genotyping. Thresholds quoted to the hundredth of a ng/mL in 123 retrospective patients with 35 events cannot be transferred as they stand and require prospective validation.

Analysis by Dr Thibaut Benquey