Integrated Mechanistic Model of Minimal Residual Disease Kinetics With Venetoclax Therapy in Chronic Lymphocytic Leukemia

Abstract

Minimal residual disease (MRD) is an important emerging clinical end point in chronic lymphocytic leukemia (CLL). The objective of this research was to develop an integrated mechanistic model to evaluate the impact of venetoclax‐rituximab combination therapy on MRD kinetics. Using data from 435 patients with relapsed or refractory CLL, an integrated model was developed and validated that accounted for venetoclax dosing and pharmacokinetics, rituximab treatment, absolute lymphocyte count, and blood and bone marrow (BM) MRD data. Simulations of venetoclax‐rituximab (six cycles) combination predicted the proportion (90% confidence interval) of patients with BM MRD below 10−4 to be 57% (54–61%) and 63% (59–67%) at 12 and 24 months of treatment, respectively. Continued venetoclax treatment to 48 months only increased the predicted rate of negative BM MRD to 66% (63–70%). These results indicate that treatment with venetoclax‐rituximab combination for a finite 2‐year period would nearly maximize the rate of negative BM MRD (< 10−4). Preliminary clinical data agree with these predictions and more long‐term follow‐up data are awaited to confirm the same.

Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials

“…This interaction can at least partially explain the selection of a higher venetoclax dose of 800 mg in combination with bortezomib and carfilzomib in patients with MM than the 400-to 600-mg doses approved in CLL and AML. [27][28][29][30][31] We noted that bortezomib and carfilzomib are primarily taken by patients with MM; hence, the effects of these comedications captured by the model might be attributed to disease population. We tested a model using MM as the covariate on CL/F in place of bortezomib and carfilzomib; this model estimated that the MM population would have lower CL/F compared to other populations with hematological conditions.…”

Chronic lymphocytic leukemia prognostic models in real life: still a long way off

“…Risk stratification largely focuses on pretreatment variables. However, post-treatment biomarkers such as minimal residual disease (MRD) assessment are gaining interest [36][37][38]. Achieving undetectable MRD after receiving therapy affects PFS and OS [38].…”

A microdosing framework for absolute bioavailability assessment of poorly soluble drugs: A case study on cold‐labeled venetoclax, from chemistry to the clinic

“…15,16 The relationship between venetoclax exposure and clinical responses has been previously desrcibed. [17][18][19][20] However, venetoclax absolute bioavailability has not been assessed. In this article, we present an end-to-end case study on using a sterile, IV solution of 13 C labeled microdose for evaluating the absolute bioavailability of venetoclax, from synthesis to the clinic.…”

“… 15 , 16 The relationship between venetoclax exposure and clinical responses has been previously described. 17 , 18 , 19 , 20 However, venetoclax absolute bioavailability has not been assessed. In this paper, we present an end‐to‐end case study on using a sterile, i.v.…”

“…Venetoclax is predominantly metabolized by the CYP3A4 enzyme 15,16 . The relationship between venetoclax exposure and clinical responses has been previously described 17–20 . However, venetoclax absolute bioavailability has not been assessed.…”