Q: What data guide the sequencing and/or combination of novel agents for CLL?

We have strong data to support the use of ibrutinib as first-line treatment in patients with CLL, followed by venetoclax in those who progress on ibrutinib. Very few data are available on the reverse sequence (ie, ibrutinib after venetoclax). 

Anderson et al retrospectively reviewed data from the first 67 consecutive patients with relapsed/refractory CLL treated with venetoclax, and 6 out of 8 patients with progressive disease on venetoclax were treated with ibrutinib. In the MURANO study of venetoclax plus rituximab in relapsed/refractory CLL, there was a subset of 8 patients in the venetoclax plus rituximab arm who received ibrutinib for progressive disease, but, again, these data are so limited that they are almost anecdotal. Most people would use ibrutinib followed by venetoclax, and, as previously noted, we do have robust data on that sequence. The 2018 trial by Jones et al was designed to evaluate the efficacy and safety of venetoclax in patients who were resistant to ibrutinib. There was a high rate of 17p deletion and/or mutated TP53 in this trial, which is indicative of prior treatment with chemotherapy/chemoimmunotherapy, and, so, this was a very high–risk group, many of whom had had multiple lines of prior therapy. Median progression-free survival was reasonably durable with venetoclax in this trial, given the incredibly resistant population. It was also interesting that some patients actually achieved minimal residual disease undetectability. This is very impressive given that this was venetoclax monotherapy rather than a combination. 

While we know that you can get good response with venetoclax after ibrutinib, we do not have much data about the reverse. The choice of sequence might also be influenced by the desire for a time-limited regimen (eg, in a patient who relapsed after fludarabine, cyclophosphamide, and rituximab [FCR]). However, if you are trying to decide treatment based on which regimen gives you the longest remission in the relapsed setting, we do not really have that data because the study populations were different (ie, RESONATE vs MURANO). At this point, it is uncertain where venetoclax/rituximab is going. If, at some point, we have a treatment that is shown to have a much longer response duration, I am not going to pay as much attention to sequencing. I am going to go with the agent that provides a longer duration. 

To date, there are limited data on the optimal sequencing of novel agents in either the frontline treatment of CLL or in relapsed/refractory patients. There are data on the use of venetoclax in patients who have received ibrutinib; however, prospectively, there are almost no data on the use of venetoclax prior to ibrutinib. There are quite compelling data showing that venetoclax, even as a monotherapy, has a high response rate, with a sizable minority of patients achieving undetectable minimal residual disease in a heavily pretreated patient population that has received ibrutinib. Our group has recently identified approximately 300 patients who have discontinued venetoclax and have gone on to receive ibrutinib at some point; this is a unique retrospective data set, and we have submitted the data to the American Society of Hematology, but the results are not yet published.

Double or triple venetoclax-based combinations with ibrutinib and/or obinutuzumab are being studied, but, in these clinical trials, something to watch out for are the proportions of patients who are able to receive full doses of each drug. If you have large numbers of patients having to reduce doses of 1 or both of the drugs in a combination, it opens up questions about whether it is better to be on a single agent at a full dose or on multiple agents at reduced doses. Efficacy data would have to be very compelling to offset my impression thus far that toxicity profiles may be difficult to manage. Moreover, there are not really any controlled data to support the use of these combinations as a standard of care.

We still do not have convincing data sets with venetoclax first, as compared with ibrutinib first followed by venetoclax, for which we have prospective clinical trial data. The sequencing scenario of FCR followed by multiple rounds of venetoclax is something that I think will definitely happen at our institution, and this should ultimately help to answer several important questions. We have a large number of patients treated with FCR who will be relapsing, and they may choose time-limited therapy again, opting for something such as venetoclax plus rituximab. Similar questions arise for these patients and for those who received venetoclax plus obinutuzumab as frontline therapy and subsequently relapse: How long can they get venetoclax repeatedly before they go on to a Bruton tyrosine kinase inhibitor, and how does that impact their outcome? We do not have any idea yet, but those are possible scenarios.

With respect to the venetoclax-based combinations for relapsed/refractory disease, the regimen of venetoclax plus ibrutinib is active, although some of the adverse events such as neutropenia or gastrointestinal events may be magnified. In the trial of the triplet regimen of obinutuzumab, ibrutinib, and venetoclax reported by Rogers et al, the hematologic toxicity was impressive and there were many complete remissions with incomplete bone marrow recovery, indicating persistent myelosuppression.