Paolo Ghia, MD, PhD: With so many treatment options in chronic lymphocytic leukemia [CLL] now, one of the major dilemmas is how to sequence them. As we know, and we knew this in the past, we always have to think about the treatment of our patient while thinking ahead about what we want to do next since we know in that, in most cases, patients will eventually relapse.

In the past, we were used to using immunochemotherapy, so we were rescuing our patients with a BTK [Bruton tyrosine kinase] inhibitor, in particular ibrutinib, because this was the first and only viable option. We also had idelalisib plus rituximab which was much less well tolerated. Venetoclax monotherapy was possible to use only after 1 line of immunochemotherapy and 1 line of BTK inhibitor. We now have many other options. In particular, we have BCL2 inhibitors in combination with rituximab in the relapsed/refractory setting or the combination of venetoclax plus rituximab in the first-line setting.

We have to decide how to start and how to rescue the patient who will progress. At the moment, with the data we have available, the patients with high-risk prognostic features, particularly TP53 aberrations, benefit much more in the long term by BTK inhibitors, in particular by continuous treatment with ibrutinib as shown in the update after 6 months in the study by the NCI [National Cancer Institute] that was recently published.

For patients with unmutated immunoglobin genes [IGVH], with a fixed-duration treatment like venetoclax/obinutuzumab, the patients tend to relapse earlier than patients with mutated IGVH genes, so these patients will probably benefit more with ibrutinib monotherapy in continuous treatment. Patients with mutated IGVH genes are those who can benefit most from a fixed-duration treatment, so if they are young enough, you can still propose FCR [fludarabine, cyclophosphamide, and rituximab]. All patients might benefit from fixed-duration treatment with venetoclax plus obinutuzumab.

How you save them is, of course, dependent on what you use in the first-line setting. If you use ibrutinib, then you can save them with the venetoclax plus rituximab. If you use venetoclax plus obinutuzumab, then you can still rescue them by again treating with a venetoclax-based regimen if they had a longer remission, or you can switch to a BTK inhibitor.

In the case of patients with unmutated IGVH genes, I would still prefer to use continuous treatment at the moment. They could also be treated with a fixed-duration of venetoclax plus obinutuzumab, and in this case, if and when the patient relapses, which seems to be happening much earlier than patients with mutated IGVH genes, we might again try to treat them with the venetoclax plus obinutuzumab treatment, so this would prolong the overall response to this class of drugs.

Regardless of the type of treatment that you are using, the first key concept is that patients should be kept on the treatment that you have chosen for as long as possible. You have to try to manage the adverse events in the best way possible; it is a pity to stop treatment for an adverse event if it is not unbearable because in that case, we are also wasting 1 line of treatment.

Second of all, particularly in the case of continuous treatment, if you are forced to stop a treatment because of an adverse event, remember that the patient can enjoy a treatment-free interval even after discontinuing ibrutinib before they need another treatment. The patient should not be switched immediately from one type of therapy to the next if they are intolerant to the previous therapy.

In case of refractoriness, which can happen of course, a patient on ibrutinib, for example, may slowly progress, so you see an increasing lymphocyte count and increasing lymph node size. Again, the patient should not be switched immediately to another therapy. They should definitely not discontinue the therapy because the disease can flare, and they can have a much faster progression. We should try to keep the patient on the treatment for as long as possible because part of the leukemia is still responding to the BTK inhibitors, and only a small clone is possibly becoming refractory. At that point, if allowed by your regulations, you can embrocate the 2 drugs in order to keep the patient on the treatment, or you otherwise stop the BTK inhibitors a bit earlier than usual before they have full-blown disease, allowing the possibility of ramping up the venetoclax at the beginning, with a lower dose to control the disease.

Stephan Stilgenbauer, MD: In the relapsed/refractory setting, the risk features of the disease, in particular the genetic characteristics, are important. We know that the novel agents such as BTK inhibitors or BCL2 inhibitors provide some good benefit for the patients with high-risk disease features such as unmutated [IGVH] genes, TP53 mutations, or 17p deletions by FISH [fluorescence in situ hybridization] testing.

Nevertheless, we know that with BTK and BCL2 inhibitors, the outcomes of patients with a 17P deletion appear to be worse. For this patient group, we need potential new combination approaches or new single-agent developments.

On the other hand, we know that there are specific resistance mechanisms toward the novel agents. For instance, when patients relapse after long-term treatment on a BTK inhibitor, we know that there are specific mutations in BTK or in the immediate next downstream signaling molecule, PLC gamma-2. These resistance mutations confer refractoriness of the disease toward BTK inhibitors, so patients who are relapsing on a BTK inhibitor should be tested for these mutations because if the mutation is present, these patients should be switched to a BCL2 inhibitor or other class of agent treatment.

On the other hand, we know that among patients who relapse on long-term BCL2 inhibitor treatment, there can be BCL2 mutations that again mediate specific resistance to the class of BCL2 inhibitor treatment such as venetoclax. When this mutation is found, it is reasonable to switch this patient to a BTK inhibitor because there is no evidence that there is cross-resistance between those 2 different classes of mutations.

The treatment landscape is becoming a bit more complicated, or to phrase it positively, you could say that there are more options available. In the relapsed setting, it is again important to determine the genetic disease characteristics and the specific mutations in BCL2, BTK, or PLC gamma-2 that may arise when treating those patients with these specific inhibitors.

Jennifer Brown, MD, PhD: Treatment sequencing remains a challenge in CLL because we do not have any prospective data to really address it, although some of the studies have been modified to try to collect that data. For a patient who receives frontline chemoimmunotherapy, there are no data for choosing between a BTK inhibitor vs venetoclax/rituximab based on the MURANO trial. This is usually a decision based on patient preference for time-limited therapy vs continuous therapy. I may favor the time-limited therapy, particularly in the lower-risk patients who are likely to get the long-term benefit, but there is also high efficacy of that regimen even in deletion 17p patients in the relapsed setting.

We do not know much about the selection yet. There are prospective data for the use of venetoclax following ibrutinib, whereas there are no prospective data for the use of ibrutinib after venetoclax, but we now have probably 3 to 4 real-world studies suggesting high response rates with ibrutinib after venetoclax. We do not have long-term follow-up of those, so we do not know what the progression-free survival is, with the exception of 1 small study from Australia where the progression-free survival was about 3 years, which looked comparable in these heavily pretreated patients to what we saw in the phase 1 study with ibrutinib. I found that study particularly reassuring that it is reasonable to use venetoclax/rituximab and save the BTK inhibitor for later, but there remain many unanswered questions.

Transcript edited for clarity.