Time-Limited Therapy With Drug Cessation Feasible in CLL

John F. Seymour, MBBS, PhD

Targeted agents are here to stay when it comes to chronic lymphocytic leukemia (CLL), said John F. Seymour, MBBS, PhD. Additionally, combination therapies, as demonstrated by the phase III MURANO trial, can achieve deeper responses and enable the use of time-limited therapy in this patient population.

“The difficulty with all of the novel agents [being used as] single agents, is that they need to be given continuously until progression; that's because the complete remission rate, and particularly, the undetectable MRD (uMRD) remission rate as single agents for all of [these options] are relatively low,” said Seymour. “If we're to achieve time-limited therapy, we need to achieve undetectable MRD to allow treatment to be stopped.”

MURANO was the first phase III randomized trial to evaluate the combination of venetoclax (Venclexta) and rituximab (Rituxan) compared with bendamustine plus rituximab (BR) in 389 patients with relapsed/refractory CLL. Patients were administered venetoclax for 2 years and rituximab for the first 6 months, or 6 cycles of bendamustine plus rituximab for the duration of 6 months.

Results of the primary analysis showed that time-limited treatment with venetoclax and rituximab was associated with an 84% reduction in the hazard for disease progression or death at 3 years versus rituximab and bendamustine.¹ Based on these data, the European Commission approved the combination in November 2018 for the treatment of patients with relapsed/refractory CLL following at least 1 prior therapy.

The FDA had granted an accelerated approval to venetoclax for patients with CLL or small lymphocytic lymphoma (SLL) harboring a 17p deletion [del(17p)], following at least 1 prior therapy in 2016. This transitioned into a full approval in June 2018 for patients with CLL/SLL, with or without del(17p), following at least 1 prior therapy. Simultaneously, it was approved for use in combination with rituximab in the same patient population.

In an analysis presented at the 2018 ASH Annual Meeting, investigators evaluated the benefit of venetoclax and rituximab in patients on study at a median follow-up of 36 months.² Results showed that continued substantial PFS and OS benefits were observed with venetoclax treatment. Additionally, the rate of CLL progression after 1 year of completing venetoclax was 13%, supporting the feasibility and safety of a time-limited duration of the combination treatment.

“The combination of venetoclax and rituximab is able to achieve uMRD,” said Seymour.

OncLive: How was the MURANO trial designed?

In an interview with OncLive, Seymour discussed the clinical implications of the MURANO trial and highlighted the feasibility for time-limited therapy and its benefits for patients with CLL.Seymour: MURANO [was a trial with] a superiority design. It was randomized [trial that tested the venetoclax combination] head-to-head in a 1:1 fashion against BR. Initially, there was no crossover built into the study, so patients who progressed on either arm then received treatment at physician’s discretion.

What were the results presented at the 2018 ASH Annual Meeting?

The trial has now been modified such that there is a crossover. Patients progressing on BR will receive venetoclax/rituximab, and those patients progressing after withdrawal of venetoclax will be retreated with venetoclax/rituximab. That amendment will give us more detail about subsequent therapy, and particularly, response to retreatment with venetoclax-based therapy.The results of the MURANO study at initial analysis had been published in the New England Journal [of Medicine] in 2018. The superiority [data]—in terms of PFS and higher rates of uMRD—for the venetoclax combination have already been established and published.

The main emphasis of the presentation [at the 2018 ASH Annual Meeting] was the outcome of patients in the venetoclax/rituximab arm after drug cessation. We now have nearly 12 months of median follow-up data. In all patients, regardless of MRD status, who stopped venetoclax at the 2-year period, the likelihood of PFS 1 year later is 87%. This shows that as a general treatment strategy, time-limited therapy with drug cessation is feasible and safe.

What is the importance of investigating time-limited therapy and what are the benefits of it?

There are some subsets within that—and the small portion of patients who have high-level MRD positivity—have a high likelihood of disease relapse. Now, we looked back, and those patients were actually progressing on the venetoclax [combination] prior to cessation of therapy. For all of the other patients with uMRD or low-level MRD, the likelihood of disease control for the first year after treatment is very high.For me, time-limited therapy is a critical, and really, the highest priority moving forward in CLL treatment. [This is true] because of 3 main reasons. Although [events are] usually relatively low grade, the cumulative toxicity for patients on continuous therapy is significant.

What questions still need to be answered?

The second [reason], of course, is the cost. These agents are expensive, and indefinite therapy is costly for both patients and the health system. Thirdly, it's now becoming clear that with any of the targeted agents, chronic exposure is able to induce selection of resistant mutations in CLL. Therefore, limiting treatment duration is critical. To enable deep responses and cessation of treatment, we have to achieve deep responses; that means [using] a combination of therapies. That [approach] will enable time-limited therapies to move forward.[In terms of treatment duration], how long is long enough to get deep remissions, but not induce resistance? Which are the preferred agents? We don't know the answers to these questions yet. My own feeling, based on early data, is that 6 months of combination treatment is insufficient. Twenty-four months seems quite good, but we may be able to get away with less. Studies are looking at adapting that treatment duration within that time frame, and evaluating whether we can individualize duration of treatment based on the response within [a patient].

What are the key take-home messages from your research and the 2018 ASH Annual Meeting?

Then, of course, the critical question is figuring out which components should be used in that combination. One thing to me is very clear: In order to get deep remissions, venetoclax is a critical ingredient in those therapies. Will it be venetoclax and a CD20-directed antibody? Will it be venetoclax and a BTK inhibitor? Will it be all 3 agents? Those [factors] need to be sorted out through future clinical trials.For me, emerging themes from this meeting and CLL [overall], are that targeted agents are here to stay; they are more effective, they are safer, and they are less genotoxic to the cells [compared with] chemoimmunotherapy.

For the majority of patient subsets, targeted agents will be used earlier. Secondly, combination therapy achieves deeper responses, and is critical to enable time-limited therapy. Time-limited therapy for CLL is where patients, prescribers, and health systems need to move to [in the future].

References

1. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax—rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018; 378:1107-1120. doi: 10.1056/NEJMoa171397.
2. Seymour JF, Kipps TJ, Eichhorst N, 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, California. Abstract 184.