CLL Research Explores Feasibility of Time-Limited Treatment

Nicole Lamanna, MD

Although many advances have been made in improving the safety and efficacy of agents available for patients with chronic lymphocytic leukemia (CLL), researchers have put a renewed focus on how to limit the duration of the current therapies, said Nicole Lamanna, MD.

“Time-limited treatment may save on cost in a big way, and there may be a subset of patients with CLL where this is very doable,” said Lamanna, an associate professor of medicine, Hematologic Malignancies Section, Division of Hematology/Oncology at NewYork-Presbyterian/Columbia University Medical Center.

The MURANO trial was the first phase III randomized trial to evaluate the combination of venetoclax (Venclexta) and rituximab (Rituxan) compared with bendamustine plus rituximab (BR) in patients with CLL, later showing positive data on time-limited treatment.

The initial analysis showed that the majority of patients were still on study treatment at a median follow-up of 23.8 months. At the 2018 ASH Annual Meeting, investigators presented 3-year follow-up data on the long-term outcomes of patients who had completed the therapy. Results showed a sustained benefit and superior progression-free survival (PFS) and overall survival with the venetoclax combination compared with BR.¹

A total of 389 patients received either venetoclax and rituximab (n = 194) or BR (n = 195). As of May 2018, all patients were off treatment. The estimated 3-year PFS rate was 71.4% with venetoclax and rituximab compared with 15.2% for patients treated with BR. The benefit with the venetoclax/rituximab combination was observed across all clinical and biological subgroups.

Another follow-up analysis looked at patients who stopped venetoclax at 2 years and tested for minimal residual disease (MRD), added Lamanna. Results showed a very significant correlation between virtually undetectable MRD and prolonged PFS.²

OncLive: Please provide some background to the MURANO trial.

In an interview with OncLive, Lamanna highlighted the latest MURANO data in CLL, delving into the need for more studies to test the feasibility of time-limited treatment in this patient population.Lamanna: MURANO was a study that enrolled patients with relapsed/refractory CLL and looked at the use of venetoclax and rituximab versus BR. This was a follow-up to a phase I study, which evaluated the combination of venetoclax and rituximab in these patients, and assessed its safety and tolerability. Once that was assessed, of course, investigators went on to compare it with a chemoimmunotherapy arm, namely BR, because this a frequently used combination in the United States. These data were initially presented in 2017, and this year we presented the 3-year follow-up. This trial looked at having venetoclax stopped; it is one of the first trials looking at a fixed-duration therapy with venetoclax.

Many of us are looking at how we can limit the oral therapies that we are using. [When] some of these newer, novel therapies such as ibrutinib (Imbruvica) [are approved], we are using them indefinitely for patients with CLL. How can we look at not only having great efficacy but then limiting the therapy?

What were the updated data presented at the 2018 ASH Annual Meeting?

In other words, [patients] can stop these oral therapies, have a long response, and their time to next treatment will be much longer. This is what we used to do with chemoimmunotherapy—we would give 6 cycles of BR and [the patient] would be done, regardless of response.This was a 3-year follow-up, and the results were very significant. We showed that the PFS with venetoclax and rituximab continued to hold very well at approximately 71% versus BR, which was about 17%. The other follow-up was looking at the patients who stopped venetoclax at 2 years. We were looking at MRD with venetoclax therapy, breaking down the data into undetectable MRD, low MRD, and high MRD. There was a very significant correlation between the patients with undetectable MRD and being in long-term remission.

Where is future research exploring fixed-duration treatment headed?

One question that arises from these data is whether 2 years of venetoclax is enough—especially for patients who still have a lot of disease at the time. There were more relapses in that subgroup. The PFS still looks great, but there is no question that patients with high levels of detectable disease will relapse quicker. We need longer follow-up on these data to see how these PFS curves hold up, and to see whether there are subsets of patients who break out and would benefit from longer duration of therapy. However, this is a very good study showing that you can do fixed durations of a drug like venetoclax.Thankfully, there seemed to be a lot of presentations at the 2018 ASH Annual Meeting looking at different combinations. How do we combine these novel therapies together? What about venetoclax and ibrutinib, and the different chemoimmunotherapies? What is the optimal regimen to look at for a fixed duration? Ultimately, everyone wants to know what the time to next treatment is for the patients who do well on a fixed duration of treatment. Could you then reintroduce the drug later on or will patients develop resistance? These are all very important questions.

We are starting to get some mature data in terms of follow-up. MRD is something we always looked at with chemoimmunotherapy regimens, but it is something we never pushed. Our traditional therapies were already fixed durations. One major issue you have to keep in mind is cost; these regimens are very expensive. When patients are started on them, they are started indefinitely unless they progress or have a severe adverse reaction. Newer therapies are getting approved all the time, and most of us want to continue focusing on fixed duration.

References

1. Seymour JF, Kipps TJ, Eichhorst B, et al. MURANO trial establishes feasibility of time-limited venetoclax-rituximab (VenR) combination therapy in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 184.
2. Kater AP, Hillmen P, Eichhorst B, et al. First prospective data on impact of minimal residual disease on long-term clinical outcomes after venetoclax plus rituximab versus bendamustine plus rituximab: phase III MURANO study. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 695.