Preliminary data suggest that BCL-2 inhibition looks promising in the treatment of patients with MCL. As reported by Davids et al in a 2017 phase 1 study, 28 individuals with MCL received single-agent venetoclax. The response rate was in the 75% range and the durability of the responses was approximately 12 to 18 months. These outcomes are comparable to those achieved with Bruton tyrosine kinase (BTK) inhibitors, or perhaps are slightly inferior, although direct comparisons are difficult to make due to the small number of patients studied. I think that venetoclax appears to be promising enough in MCL that the generation of an appropriate dataset could lead to US Food and Drug Administration approval for this indication. It is certainly promising enough to support testing in combinations with other agents.

An important aspect of venetoclax to discuss is its mechanism of action. Venetoclax diminishes levels of BCL-2 inside of malignant cells, lowering the apoptotic threshold and making the cell more willing to die. Venetoclax will partner well with many of the other lymphoma agents by forming the basis of an effective “1-2 strategy,” with venetoclax lowering the apoptotic threshold and another agent coming along to finish the cell off. Within our ECOG-ACRIN foundation (PrECOG), we are about to start a study of venetoclax administered in combination with bendamustine and rituximab as part of the initial therapy for older patients with MCL. We already know that bendamustine-rituximab is an effective combination for older patients with MCL, but there is much room for improvement. Venetoclax will be administered for 10 days with each 28-day cycle of bendamustine-rituximab. The primary end point is the complete response rate to the combination therapy.

Combining venetoclax with BTK inhibitors is also intuitive, and the hope is that this may result in greater complete response rates and longer durations of response than those seen with BTK inhibitor monotherapy. In addition, some patients who have not responded to BTK inhibition alone may respond to the combination. For example, if you administer a BTK inhibitor to 100 patients with MCL, it is likely going to work in 70 patients and not work in 30. Of the 70 patients for whom it worked, approximately half will relapse within 12 months, meaning that they developed a resistance to BTK inhibition. By combining BCL-2 inhibitors such as venetoclax with BTK inhibitors, we may be able to prevent or delay the emergence of these resistant clones.  Studies evaluating this combination are underway and some data have already been published, showing promising early results.