Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

Abstract

The objective of this research was to characterize the venetoclax exposure‐efficacy and exposure‐safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low‐dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure‐safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure‐efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure‐response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400‐mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure‐response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

Population Pharmacokinetics and Exposure–Response Analyses for Venetoclax in Combination with R-CHOP in Relapsed/Refractory and Previously Untreated Patients with Diffuse Large B Cell Lymphoma

“…Previous studies have evaluated the venetoclax ER relationships in subjects with CLL, NHL, or multiple myeloma [20][21][22][23][24]. ER analyses were performed to confirm the dose selection of venetoclax in combination with R-CHOP chemotherapy for future studies.…”

Semimechanistic Modeling to Guide Venetoclax Coadministration with Ritonavir and Digoxin

“…The RTV-VEN model predicted fourfold to eightfold dose adjustments of venetoclax when combined with ritonavir to be adequate based on venetoclax exposure-response relationships assessed in subjects with CLL, acute myeloid leukemia, non-Hodgkin's lymphoma, or multiple myeloma. [25][26][27][28][29] To avoid the risk of lymphopenia, an on-target effect of venetoclax, a single subtherapeutic dose (100 mg) of venetoclax was studied in female healthy volunteers in the digoxin drug-interaction study. 30 In that study, digoxin C max and AUC were increased by 35% and 9%, respectively, with no changes in half-life or renal clearance.…”

Overexpression of annexin A5 might guide the gemtuzumab ozogamicin treatment choice in patients with pediatric acute myeloid leukemia

“…45,46 Venetoclax, an inhibitor of BCL2 gene mutation, has been used in elderly patients with AML. 47 The effective rate of single-drug therapy in patients with recurrence was about 20%, and combined with hypomethylated drug therapy, 60%. 48 Furthermore, GO can be used in AML induction chemotherapy to improve OS and relapse free survival (RFS) and reduce recurrence rates.…”