<p>The expanding role of venetoclax in chronic lymphocytic leukemia and small lymphocytic lymphoma</p>

Abstract

The BCL-2 protein family members inhibit cellular apoptosis, and their overexpression represents a common survival adaption in cancer. Recently, a selective BCL-2 inhibitor ABT-199, venetoclax, has demonstrated remarkable activity in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), both as a single agent and in combination with anti-CD20 immunotherapies, such as rituximab. In this article, we review the development and latest clinical data that have led to the expanded approval of venetoclax with rituximab in relapsed/refractory CLL/SLL. We also discuss ongoing and future clinical trials designed to evaluate the efficacy of venetoclax in previously untreated patients and to investigate venetoclax combinations with inhibitors of B-cell receptor signaling pathway. These studies hope to offer an expanded list of chemotherapy-free regimens for patients with CLL/SLL.

Quantification of Venetoclax for Therapeutic Drug Monitoring in Chinese Acute Myeloid Leukemia Patients by a Validated UPLC-MS/MS Method

“…Each concentration was analyzed in three replicates and the precision for each calibrator with RSD ranged from 0.38% to 5.35%. According to several literatures, the plasma concentration of venetoclax varied from 30 to 4000 ng/mL in human (including healthy volunteers, chronic lymphocytic leukemia patients, and small lymphocytic lymphoma patients) across the dose levels (100–600 mg) [ 28 , 29 , 30 , 31 ], indicating that the calibration curve is capable of measuring the concentration of venetoclax in human plasma by encompassing both peak and trough concentrations.…”

“…Each concentration was analyzed in three replicates and the precision for each calibrator with RSD ranged from 0.38% to 5.35%. According to several literatures, the plasma concentration of venetoclax varied from 30 to 4000 ng/mL in human (including healthy volunteers, chronic lymphocytic leukemia patients, and small lymphocytic lymphoma patients) across the dose levels (100-600 mg) [28][29][30][31], indicating that the calibration curve is capable of measuring the concentration of venetoclax in human plasma by encompassing both peak and trough concentrations. The calibration curve of venetoclax was validated at seven points over the concentration range of 25-8000 ng/mL covering the plasma therapeutic range with a coefficient of correlation (r 2 ≥ 0.997, Figure 2), following the regression equation (y = 0.0003816x + 0.05653).…”

Treatment strategies for a rapidly evolving landscape in chronic lymphocytic leukemia management

“…33 The rampup takes 5 weeks of close monitoring, which may be inconvenient to patients. 9,12,32 In Phase Ib-III studies of first-line venetoclax combination regimens, the most frequent grade 3-4 AE was neutropenia, although neutropenic sepsis rates were low (Table 2). 3,33,34…”

Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors

“…Moreover, patients with p53/ATM mutations do not respond to CIT and alternative therapeutic strategies are required. In these cases, patients may be treated with newer targeted agents, including BCL2 inhibitors such as venetoclax to reverse BCL2-mediated suppression of apoptosis [23] or inhibitors directed against BCR-associated signaling kinases, including ibrutinib (discussed in detail below) [24].…”