In the near future, we will see a greater use of novel combinations with the available agents, including venetoclax and Bruton tyrosine kinase (BTK) inhibitors with or without an anti-CD20 antibody, and treatment decisions will be based on pretreatment characteristics and measures of response, such as minimal residual disease. There is movement toward using these parameters to predict an optimal treatment duration (eg, continuous, 6 months, or 1-2 years) and then to tailor therapy accordingly. And it is great news that noncovalently bound BTK inhibitors are being developed for patients who become resistant to irreversible BTK inhibitors, often via mutations in cysteine 481. The noncovalently bound BTK inhibitors are likely to become an option in the near future, and they might have an expanded role down the line.

We are currently able to control CLL to the extent that the number of patients requiring a cellular therapy approach right now is very small, but this is an area of investigation. One challenge with cellular therapy in CLL is that T cells are very dysfunctional from the disease, so strategies to improve the fitness of T cells in cellular therapy are being explored. There is also research focused on allogeneic chimeric antigen receptor (CAR) T cells and allogeneic natural killer cells. There is a lot of hope, but still much more work to be done. Thankfully, the small-molecule and antibody approaches have advanced the field tremendously and have improved survival so much that the need for cellular therapies is becoming smaller and smaller in CLL.

We have 3 main classes of drugs that are very effective in patients with CLL: BTK inhibitors, anti-CD20 antibodies, and BCL2 inhibitors. Optimizing combination therapy and understanding the best ways to sequence existing agents are priorities that will give shape to the future. We are now in the position to begin studying different combinations and determining whether it is best to combine agents or to give them in sequence. Answering questions about sequential vs combination therapy is not always quick or easy in the context of clinical trials, and the use of doublet vs triplet therapy is being studied. Currently, I am hesitant to recommend triplet therapy until further data are available. 

I also think that there will continue to be a reengineering of existing technologies. We will be looking to improve BTK inhibition with the noncovalent inhibitors and to improve anti-CD20 antibodies, possibly to include the use of bispecific antibodies. And then, some research is likely to be directed toward newer targets such as CD19, with CAR T-cell therapy, and, potentially, CD37. 

I agree that there will be reengineering and continued work to improve our current therapies. For instance, ibrutinib is a great drug, and we now have second-generation molecules that are more selective and have better side-effect profiles. Strategies to integrate the second- and third-generation molecules are currently in development. The protein degraders that get rid of BTK are also exciting. 

With BCL2 inhibition, I think that there is substantial room for improvement. Venetoclax has a very long half-life. It would be great if we could decrease the half-life, preserve the same benefits, and, perhaps, attenuate the immune suppression, in addition to tweaking the targets, particularly as we think of patients with high-risk CLL and TP53-independent mechanisms. I think that we have a lot of room to explore alternative targets, especially for patients in small, but clinically significant, molecular subsets. The high-risk group in CLL is comprised largely of patients with TP53 aberration, but there may be patients with less common genetic features for whom therapy should be further tailored and individualized.

Finally, to me, one of the most exciting parts is figuring out how we can harness the immune system with better antibodies, technologies, and cellular therapy with CAR T cells or natural killer cells. The immune system is such a powerful tool.