To me, venetoclax plus obinutuzumab has become the most substantial frontline therapy for patients with most forms of CLL. I offer it to all my patients, with the possible exception of those who have 17p abnormalities. I feel that these individuals are at high enough risk that they might be better off with a BTK inhibitor in continuous treatment. The advantage of venetoclax plus obinutuzumab is that it is time limited with 1 year of treatment, and that is popular with many patients. However, many of my patients have logistical challenges with getting to the office for the ramp-up that is required with venetoclax, so they often opt for a BTK inhibitor instead.

Patients generally prefer a BTK inhibitor as a single agent and not in combination with a monoclonal antibody because they do not want to come into the office to get infusions. However, emerging data from the phase 3 ELEVATE-TN trial suggest that there may be a progression-free survival advantage and a trend toward an advantage in overall survival with adding obinutuzumab to acalabrutinib. If that is confirmed, then we will need to think about strongly encouraging patients to get the combination.

The combination of a BTK inhibitor with venetoclax, an all-oral regimen, is interesting to me. A number of these combinations have shown efficacy in terms of complete remission and progression-free survival in clinical trials. The difficulty is that no US Food and Drug Administration (FDA)–approved regimen is using this strategy right now, and it can be quite expensive to use both a BTK inhibitor and venetoclax.

There are 3-drug regimens in development. The BOVen regimen (ie, zanubrutinib, obinutuzumab, and venetoclax) has a very high complete remission rate, response rate, and measurable residual disease negativity rate. However, it is not yet clear whether using a 3-drug regimen is superior to using a 2-drug regimen, and we need further follow-up.

The question of how best to use small-molecule drugs in sequence and in combination is important. For example, after a patient has had prior exposure to both venetoclax and a BTK inhibitor as single agents, can we get more durable remissions by combining them? Anecdotal experience and data from small series suggest that this may have efficacy, and I have done it in my clinical practice.

An exciting option on the horizon is combination therapy with the noncovalent BTK inhibitor pirtobrutinib. The phase 3 BRUIN CLL-322 study is currently underway in the relapsed setting and is evaluating the addition of pirtobrutinib to the MURANO regimen, which is venetoclax plus rituximab for 2 years. Do we gain anything by adding pirtobrutinib to that regimen? We do not know the answer yet, but it is an important question.

There are still many unanswered questions regarding how best to use these small molecules in combination therapies. Our backbone regimens have gotten so good that it is difficult to prove the value of adding another agent to them. The level of treatment has improved dramatically in CLL, which is good news for patients.