The most important factor to consider when choosing second-line treatment is what the patient received in the frontline setting. If they received chemotherapy, then the conversation is essentially the same as it would be if we were discussing novel agents in the frontline setting (ie, the choice is between a Bruton tyrosine kinase [BTK] inhibitor or a venetoclax-based combination). If the patient received a BTK inhibitor as first-line therapy, the clear choice for most patients would be venetoclax for second-line therapy. However, it is more complicated for those who received frontline venetoclax. Since the venetoclax/obinutuzumab regimen is a fixed-duration frontline regimen, you have the option of using venetoclax again rather than automatically switching to an alternative class, such as BTK inhibitors. Although I have not yet had a patient progress on venetoclax, I would likely base my decision of whether to reuse venetoclax on the durability of response to the first course of venetoclax. If they achieved a long duration before relapsing, I would likely be inclined to use venetoclax again because I like the idea of exhausting the effects of 1 drug before switching to another agent.

We have had some long-term follow-up data from the MURANO trial suggesting that patients who have received prior chemotherapy can have very durable responses with venetoclax/rituximab. There are also data indicating that these patients do very well when they subsequently go on a BTK inhibitor. Longer-term follow-up data on durability of response will be useful in steering us in a direction of which regimen we would prefer in these situations.

I agree that the duration of response is a key factor when deciding whether to re-treat with venetoclax after frontline venetoclax. If a patient got only 1 year of remission from venetoclax plus obinutuzumab, I would likely not reuse venetoclax; however, if they got 4 years, I would. We do not know where the exact inflection point is regarding when to reuse venetoclax or when to switch to a BTK inhibitor, but it is probably somewhere in between these 2 response durations. This is an area where additional prospective data on venetoclax retreatment are urgently needed.

Although we do not have data yet on the genetic factors that influence the retreatment decision, one potential factor is the patient’s IGHV mutation status, as those with unmutated IGHV may be less likely to have durable benefit from a second round of venetoclax/obinutuzumab. For these patients, I would steer more toward a BTK inhibitor in the second line of therapy, whereas those with mutated IGHV might be more likely to benefit from a second round of venetoclax/obinutuzumab in hopes of getting a second durable response. It is also worth noting that we generally do not recommend chemoimmunotherapy for any patient in the relapsed/refractory setting. The 5-year follow-up data from the MURANO study have continued to show an approximate 20% improvement in overall survival for venetoclax/rituximab compared with bendamustine/rituximab. Although this study included few patients who had progressed on frontline BTK inhibitor therapy, we do have another prospective study showing benefit from venetoclax in the post–BTK inhibitor setting. An interesting situation to navigate is how to treat patients who have toxicity on a BTK inhibitor, particularly if that BTK inhibitor is ibrutinib. One can either try another BTK inhibitor or switch to venetoclax. For me, the choice depends on the nature and the timing of the toxicity. If it is a serious event, such as a life-threatening bleed, I would switch the patient to venetoclax. However, if the patient is having nagging joint aches or myalgias, I might switch them to acalabrutinib if ibrutinib dose reduction does not help. 

Since patients can acquire 17p deletion and TP53 mutations at relapse and progression, it is important to recheck for those abnormalities if you are switching treatment. We have also been checking for BTK and PLCG2 mutations in patients on BTK inhibitor–based therapy because that is informative. When considering a treatment regimen for patients with relapsed disease, I think that it is important to consider both short-term and long-term disease control. In the relapsed setting, patients who have 17p deletion or mutated TP53, as well as those who progress on BTK therapy, tend to have a shorter progression-free survival. Data from Jones and colleagues indicate that the median progression-free survival in patients receiving venetoclax monotherapy after progression on a BTK inhibitor is approximately 2 years. Thus, although these patients will get good disease control, it will only be for a limited time and you will need to consider their long-term options (eg, clinical trials, cellular therapy, and stem cell transplantation). One interesting possible therapy in patients who have developed resistance to either a BTK or a BCL2 inhibitor is to use combination therapy with BTK/BCL2 inhibitors. There are not any clinical trials addressing whether such combinations are effective, but they do have some theoretical appeal.