William Wierda, MD, PhD: Dr Shadman, let’s switch gears now and move to relapsed disease. You spoke a lot about the CLL14 study, which analyzed venetoclax in the frontline setting. Let’s transition to the relapsed setting and the application of venetoclax in the relapsed setting. The MURANO trial led to approval for venetoclax-rituximab in the relapsed setting and has been updated recently. Can you highlight the information from that update?

Mazyar Shadman, MD, MPH: MURANO was the study that brought venetoclax-based therapy in combination with rituximab to the relapsed setting for CLL [chronic lymphocytic leukemia]. Patients were given a chemotherapy-free regimen that was time limited—in this case, 2 years. Patients were randomized in a 2-arm study to either venetoclax-rituximab—here venetoclax started first, and a patient received that treatment for 2 years—or bendamustine-rituximab. It was not an MRD-guided study. All participants stopped at 2 years if they could tolerate and if they were responsive to treatment.

The standard arm of the study was bendamustine-rituximab, a commonly used regimen. Around 40% of patients, distributed between the 2 arms, had an abnormal TP53 deletion or mutation. The study showed both PFS [progression-free survival] and an overall survival advantage for venetoclax and rituximab, and I believe a PFS of around 86% vs 35% in the initial report. This is another situation in which achieving an MRD-negative state at the end of treatment is important for prognostic information and because that translates to a longer PFS.

At the last ASH [American Society of Hematology Annual Meeting] in 2019, Dr John Seymour presented the 4-year follow-up of the MURANO study, in which we continued to see improved PFS in the venetoclax-rituximab arm—57% vs 5%. The most important piece of that presentation, looking specifically at MURANO, was that we have clear numbers of PFS in patients who have an undetectable MRD, and that is uMRD4, with a median of 22 months being off therapy.

Eighty-six percent of patients who have uMRD at the end of treatment are PFS vs 60% in patients who are considered low MRD, which is 10-2 to 10-4 vs about 7% in patients who have more disease burden, defined as more than 10-2. The MRD achieved at the end of treatment gives valuable information on what to expect in terms of clinical progression.

The important data that came out of this long-term follow-up help us answer the question Dr Burke asked earlier, which is do we use MRD in clinical practice? In my case, my official answer would be no. I try to go with 1 or 2 years of therapy, but I have been looking at MRD because the MURANO long-term follow-up shows that the kinetic of the MRD matters. When they looked at the patients who had detectable MRD at the end of treatment, the patients had a rising MRD level before the end of therapy.

In a way, we can use MRD to predict if a patient will have relapsed CLL. If you start checking a little earlier and see the rate of the level of detectable CLL rising, you know that your patient won’t achieve an undetectable state at the end of 2 years and probably won’t achieve an undetectable state if you continue the current course of treatment. Not only will you not see improvement, but you will see more disease. Do I use that? I have. For a number of patients I started looking at their MRD a little before the end of therapy. If I see that their levels are going down, and if I can treat them for 26 months instead of 24 months and then stop and they achieved detectable MRD state, I do it. This is not based on any data, but I think most of us try to create some data for ourselves.

That’s my small project. But really, this is another discussion that I have with patients. I tell them that the whole idea of going on this therapy is to have a fixed-duration therapy. If I want to continue to chase an MRD, that may not be the smartest idea. But if I see that trend and if I feel that by treating 2 more months we can get an undetectable state, then I will. Some patients feel much more comfortable stopping treatment if they know they don’t have any detectable disease, using what we have in terms of the MRD assessment tools.

The longer follow-up of the MURANO study shows that a time-limited chemotherapy-free treatment using only 1 of the novel agents in the relapsed space is effective. We talked a lot about combinations, and it’s great to use our best drug up front and hopefully cure patients, but I also think about the situation in which a patient stops responding to both. Having a combination of venetoclax with a non–BTK [Bruton tyrosine kinase] therapy is reassuring because you know you have a very reliable drug as a backup plan. This was the MURANO summary and follow-up.

William Wierda, MD, PhD: Great, thank you.

Transcript Edited for Clarity