The B-cell receptor signaling pathway may be even more important than we previously realized, based on how readily CLL cell survival and proliferation are compromised by BTK inhibition. Far downstream of the BCL2 family members, we do see upregulation as part of the stimulation of this pathway, so there is the prospect of exploiting both direct and indirect inhibition of this pathway. There is also in vitro evidence of synergy between BTK and BCL2 inhibitors in a variety of lymphoma cell lines, including CLL. Ex vivo studies have shown that, among patients with CLL who have been treated with ibrutinib, BCL2 inhibition with venetoclax is the most effective way to kill residual CLL cells (ie, better than using other B-cell receptor inhibitors or chemoimmunotherapy). Further, mitochondrial BCL2 dependence increases with either ibrutinib or acalabrutinib, and that also suggests that BTK inhibition may synergize with BCL2 inhibition. Ibrutinib acts by withdrawing survival signals, which is suggestive of a slower effect on cell death, but there is also evidence of a more direct killing of CLL cells, especially in the first few days of treatment. Venetoclax results in a very rapid killing of CLL cells, such that tumor lysis is its primary side effect.

Most of the clinical studies evaluating BTK/BCL2 combinations have been designed with the BTK inhibitor administered first. BTK inhibition seems to prime the patient for treatment with the BCL2 inhibitor and its more direct effect on CLL cell death. There is also a debulking of the disease with BTK inhibition, which reduces the risk of tumor lysis syndrome during the BCL2 inhibitor ramp-up. In general, the BTK inhibitor is continued when the BCL2 inhibitor is added. Combined BTK/BCL2 inhibition is currently being explored, along with other chemo-free combinations, in pursuit of a minimal residual disease–based duration of CLL treatment, with the ultimate goal being disease eradication. 

From my perspective, such a regimen would be most essential as frontline therapy in 17p deleted– or TP53-mutated patients, but other high-risk patients may also benefit, as the combination likely reduces the chances of developing resistance. For patients who are relapsed or refractory, the use of BTK/BCL2 combinations may be most essential in those who have previously been treated with either drug alone. As with all treatment decisions in CLL, the use of combination vs single agent therapy would likely depend, in part, on the risk profiles of the patients. If they are IGHV mutated and have low-risk cytogenetics, I might not necessarily give them both agents because the combination does tend to produce more side effects. The side-effect profiles of the 2 drugs are generally not overlapping, which is helpful, with the exception of neutropenia and some increased gastrointestinal toxicity such as diarrhea and nausea, although the latter is usually not an issue with most patients.