Stephan Stilgenbauer, MD: When we move a bit away from frontline treatment and focus on the second-line or relapsed/refractory settings, we again have the option of novel agents available: BTK [Bruton tyrosine kinase] inhibitors, BCL2 inhibitors, acalabrutinib, ibrutinib, venetoclax in select patients, and possibly even the PI3K inhibitor idelalisib, although this is less well tolerated than the other options and is therefore not a preferred treatment choice in the second-line setting.

When it comes to making the decision in the second-line setting, there are disease characteristics, such as genetic risk factors of the disease. There are patient characteristics, such as comorbidities and co-medications, and there is the question of what the frontline therapy was. When a patient fails frontline therapy early, we do not want to repeat this therapy, but we want to switch to another class of agents.

For instance, when a patient is failing on continuous therapy with a BTK inhibitor, you are likely to switch them to a BCL2 inhibitor, such as venetoclax. On the other hand, when a patient is relapsing after fixed-duration BCL2 inhibitor treatment with venetoclax plus obinutuzumab, if disease progression is after a prolonged period of therapy, such as 3, 5, 6, or more years for instance, we could retreat this patient with a BCL2 inhibitor because the patient was off therapy for long enough. The other option would be to switch the patient to a BTK inhibitor such as acalabrutinib or ibrutinib because you want to give another class of agents an opportunity in this patient.

In other words, you have different choices, and the choice in the relapsed/refractory setting also depends on what your treatment choice in the frontline setting was. We have more experience when sequencing the novel agents by instituting a BTK inhibitor first and then going to a BCL2 inhibitor in relapse. On the other hand, the sequence may not be etched in stone, and in the future the other way around will also be investigated deeper.

Paolo Ghia, MD, PhD: We now have more options in the relapsed/refractory setting, so besides the long-standing availability of ibrutinib in terms of novel therapies as well as idelalisib plus rituximab or venetoclax monotherapy, we now have another BTK inhibitor available. It is a second-generation BTK inhibitor, acalabrutinib, as monotherapy as well as a fixed-duration treatment like a venetoclax plus rituximab for 24 months in this relapsed/refractory setting. For the acalabrutinib monotherapy, the approval has been achieved thanks to the ASCEND study, which was a phase 3 study comparing acalabrutinib monotherapy with physician choice between idelalisib plus rituximab or bendamustine plus rituximab, which are the typical second-line immunochemotherapies.

The study showed an advantage for patients treated with acalabrutinib and a good safety profile compared with idelalisib plus rituximab but also in comparison to bendamustine plus rituximab. The study showed overall good tolerance of the drug in patients in the relapsed/refractory setting, with a low frequency of atrial fibrillation, a low frequency of bleeding, and in particular no intracranial hemorrhage. For other adverse events like hypertension, myalgia, or arthralgia, which typically show up later during treatment with acalabrutinib, we need a longer follow-up than what is being shown here with only of 22 months.

When we consider an extended, fixed-duration treatment of venetoclax plus rituximab, the approval was achieved thanks to the results of the MURANO study, where venetoclax plus rituximab for 24 months was compared to bendamustine plus rituximab for 6 months. This was in the relapsed/refractory setting, and 60% of the patients were treated in the second-line setting, so the data are already quite important for the second-line treatment setting.

We now have a 4-year follow-up that confirms the advantage in terms of the sustained PFS [progression-free survival] in patients treated with venetoclax and rituximab compared to bendamustine plus rituximab. As I said, it was a typical, classic immunochemotherapy in the relapsed/refractory setting. What we learned and has also been confirmed in the update: a high proportion of patients achieve undetectable MRD [minimal residual disease] after venetoclax plus rituximab; 57% of the patients achieve undetectable MRD in the bone marrow at the end of the treatment. These are the patients who can enjoy a long-term progression-free survival that is sustained and maintained in the long run.

In contrast, the patients who do not achieve undetectable MRD or even worse, those who progress under the treatment with venetoclax plus rituximab, have a much quicker progression. Indeed, these patients can be rescued only in 55% of the cases by using venetoclax plus rituximab, though 100% of the patients can be rescued by ibrutinib by BTK inhibition. That is probably one of the limits of the fixed-duration treatment, not of the drug per se, but the drug combination, the fixed-duration treatment, which is independent of the type of response and the depth of response that the patient achieves. It would instead be nice to tailor the treatment, meaning that those who achieve undetectable MRD maystop the treatment because they can maintain their response for a long time, but those who do not achieve undetectable MRD may need to continue the treatment or even add another treatment in a much more powerful combination.

Transcript edited for clarity.