Venetoclax as a monotherapy, or even when administered with obinutuzumab, does not look very good in the high-risk CLL subset. With the addition of a BTK inhibitor, results are certainly better, but I think that this is an important investigational area. The combination of a BTK inhibitor plus venetoclax, if approved by the US Food and Drug Administration, may be of interest; however, we do not know which, if any, of the combinations that are under consideration will have durable remissions in patients with high-risk CLL. 

Aberrant p53 functioning is often associated with genomic instability. It makes sense that the more of an unstable clone that remains after treatment, the greater the chances of resistance, so I think that the eradication of disease will be important. Drawing on data from other B-cell malignancies, we have learned about a variety of mutations that are relatively rare in CLL but may still be informative. Some mutations seem to signal the ability to partially bypass a BTK inhibitor; there is a rare translocation that causes the overexpression of BCL3 and activates the NF-κB pathway. Other mutations, such as CARD11, are observed more in patients with diffuse large B-cell lymphoma, and BTK inhibitors appear to be effective. 

This situation provides an opportunity to consider other targeted drugs, drug combinations, and enrollment in a clinical trial. In thinking about high-risk CLL as an investigator, I would be more excited about adding TP53-independent agents to a BTK inhibitor with or without a CD20 antibody, as opposed to adding venetoclax. Such agents might be something broader than venetoclax, to hit not only BCL2 but also bcl-xL or several of the BCL2 family members. 

For most patients with either a TP53 mutation or 17p deletion (del[17p]), I recommend a BTK inhibitor and not venetoclax plus obinutuzumab as frontline treatment. The current data appear to be better with continuous BTK inhibitor therapy than with the time-limited approach of venetoclax. One confounding issue is the duration of therapy. It is possible that you might have better outcomes in high-risk populations if you give venetoclax for a longer period of time. In the phase 3 MURANO trial, venetoclax was given for a longer period. In this relapsed or refractory CLL population, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. Further, the 2-year progression-free survival rate among those with del(17p) was 81.5% in the venetoclax-plus-rituximab group vs 27.8% in the bendamustine-plus-rituximab group. These results appear better to me than what you might expect with a shorter duration of treatment.

Additionally, I agree with Dr Byrd that we simply do not know which combinations will produce the best outcomes in our high-risk populations. I would go even further to say that we do not yet know which 2- or 3-drug combinations will be best in any of the treatment settings that are being considered, but I am fairly confident that a BTK inhibitor should be incorporated in the first-line treatment of patients with del(17p). 

There is still reasonable uncertainty in the field regarding the optimal treatment strategy for patients with these genetic mutations. I also tend to favor a BTK inhibitor–based approach in patients with del(17p), and, for the time being, that would be primarily BTK inhibitor monotherapy. 

We are currently exploring acalabrutinib with either venetoclax or obinutuzumab in the phase 3 MAJIC trial. Additionally, interim data from the phase 3 ALPINE trial comparing the second-generation BTK inhibitor zanubrutinib with ibrutinib in adults with relapsed or refractory CLL look very promising. Of those on zanubrutinib, 11.6% had del(17p) and 8.2% had TP53 mutations; of those on ibrutinib, 12.5% had del(17p) and 5.8% had TP53 mutations. Researchers reported that zanubrutinib significantly improved response rates and delayed disease progression compared with ibrutinib. For the poor prognosis subset of patients with del(17p), the overall response rate was significantly higher with zanubrutinib compared with ibrutinib (83.3% vs 53.8%). Encouragingly, substantially lower rates of atrial fibrillation/flutter and cardiac disorders of any grade were reported with zanubrutinib than with ibrutinib. Finally, in general, when I look at the data from the phase 3 CLL14 trial of venetoclax plus obinutuzumab, I see that patients with del(17p) tended to have earlier relapses.