Treatment Options for Relapsed/Refractory CLL

Transcript:Matthew S. Davids, MD, MMSc: Traditionally, patients with relapsed CLL [chronic lymphocytic leukemia] were treated with chemoimmunotherapy for a second or third time because that’s the only therapeutic modality we have. However, we’re very fortunate now to have many different novel agents to choose from for patients with relapsed or refractory CLL. And in general, I do not recommend using chemoimmunotherapy for most patients with relapsed or refractory CLL, given the widespread use of these new targeted therapies, which tend to be equally or even more effective with less toxicity.

The agents that we can consider that have approvals in this setting are ibrutinib, venetoclax with or without rituximab, idelalisib with rituximab, and a newer PI3 [phosphoinostide 3] kinase inhibitor drug called duvelisib. All of these are viable options for our patients, and I think in terms of how we choose among them, it really depends on the individual patient.

In the relapsed or refractory setting, I generally consider all these patients to be at relatively high risk compared with the front-line setting. If patients have not previously been tested for deletion 17p or p53, I think it can be valuable to do this in the relapsed setting mainly to help guide prognosis and to identify those highest-risk patients, who may need to be planning ahead for more definitive therapies, such as allogeneic transplantation.

Venetoclax was first developed as a monotherapy, and this was explored in a large phase I trial in CLL, in which the overall response rate was about 80% and the complete response rate was about 20%. In general, the drug was quite well tolerated. However, there were some significant risks, and these included tumor lysis syndrome, which can be mitigated through a very careful dose ramp up with prophylaxis and monitoring, as well as neutropenia, which in some cases would lead to infection but actually in most cases was easily managed using growth factor support. And gastrointestinal adverse effects, which again usually were fairly easily managed.

The MURANO trial is a registrational trial that compares the standard regimen of bendamustine and rituximab with the experimental regimen of venetoclax and rituximab. In this study, bendamustine and rituximab are given for a standard 6 cycles. Venetoclax and rituximab are given for a combination of 6 months, and then the venetoclax is continued for an additional 18 months for a total of 2 years of therapy, at which point all patients would stop therapy irrespective of their response.

We’ve now seen multiple presentations and a publication on the MURANO study, and the results look quite compelling and favor the venetoclax-rituximab arm in several different ways. Importantly, in addition to the progression-free survival benefit, there was also an overall survival benefit observed, and that was updated at the ASH meeting [American Society of Hematology Annual Meeting and Exposition] this year that seems to be preserved after 3 years of follow-up.

So the presentation at the ASH meeting this year summarized the updated results of the Moreno study, and it utilizes a 24-month fixed duration therapy. I think the hope was that all patients would be able to have this fixed 24-month regimen because it’s simple to know that it’s a 2-year regimen.

However, I think what we learned at this year’s ASH meeting is that it might not be so simple. Because patients at the end of the 2 years who still had detectable MRD [minimal residual disease] ended up having clinical progression of their CLL very soon after stopping therapy.

On the other hand, patients who received this regimen and got into an undetectable MRD state, or had a low level of MRD, had a very low chance of progression; there were only a couple of progressors in that group. So I think what we’re moving toward is the idea of testing for MRD after the 2 years, and if patients are undetectable or have low-level MRD, they will cease therapy at that point. But for patients who still have detectable MRD after 2 years, consideration needs to be given to other strategies, which could include continuing venetoclax, adding on an additional agent, or switching mechanisms completely to a different drug.

So at this ASH meeting we saw a lot of additional data on the MRD results from the MURANO trial. And I think these are very influential in terms of how we think about this time point of 2 years of therapy. So we know that patients who can get to MRD undetectability, at least after a median of 10 months of follow-up off therapy, are generally still in a very good remission.

In contrast, patients who are MRD detectable at the end of those 2 years tend to progress rather rapidly. And in fact, 1 of the things that was interesting about the presentations at the ASH meeting is that were tracking the MRD testing serially every 3 months while the patients were on the trial. And 1 of the interesting things that was noted is that the patients who are MRD detectable at the end of the 2 years often had a rising of MRD while still on venetoclax therapy, whether it was at month 15 or 18 or 21 or 24.

So this actually suggests that these patients may not benefit from additional venetoclax therapy and may be actually better served by either adding a second agent or switching to a different drug altogether.

Transcript Edited for Clarity