Long-Term Data of Venetoclax, Obinutuzumab Fixed-Duration Combo Show Promise in Chronic Lymphocytic Leukemia

In an interview with Pharmacy Times, Othman Al-Sawaf, MD, titled investigator in the CLL14 study, discussed new findings released at the European Hematology Association 2022 Congress. Al-Sawaf said long-term follow-up in the CLL14 trial have found promising results for patients with chronic lymphocytic leukemia.

One-year fixed-duration treatment with venetoclax and obinutuzumab has shown improvements in progression-free survival. Can you discuss these earlier data?

Othman Al-Sawaf, MD: Thank you. So, venetoclax–obinutuzumab has been now under development and has actually been already used in regular clinical care for quite some time. The first data that have been shown for venetoclax–obinutuzumab were shown already in 2019, when we had the primary readout of the same protocol from CLL14. It's also observed that in a patient population of elderly and unfit patients with chronic lymphocytic leukemia, treatment with venetoclax–obinutuzumab extended progression free survival significantly compared to chemotherapy with chlorambucil and obinutuzumab.

And since then, venetoclax–obinutuzumab has been already widely used in regular clinical care since it was FDA and EMA approved for frontline CLL. However, given that the use is largely based on the data that we have from the first readout from CLL14, we feel it is important to continue to follow up on these patients that have been treated within this study in order to understand how their long-term outcomes are, whether there are any long-term complications or implications of this kind of novel treatments. And therefore, the data that we are showing here at the EHA meeting largely builds on this primary readout that we had and continue to look into certain details that we feel are of particular clinical relevance.

How do the new data build on these findings?

Othman Al-Sawaf, MD: The readout that we are doing now is based on a longer follow up based on the primary doubt that we had in 2019, where we saw that patients who received fixed duration venetoclax–obinutuzumab—so 12 cycles, with each cycle being 28 days long, 12 cycles of treatment with the oral Bcl-2 inhibitor venetoclax in combination with the CD20 antibody obinutuzumab, compared to 12 cycles of chemotherapy with the oral compound chlorambucil in combination with the CD20 antibody obinutuzumab. And we saw that already the progression free survival was significantly longer after venetoclax–obinutuzumab than with chlorambucil–obinutuzumab, albeit after a relatively short follow-up of approximately 28 months where we already saw that there is a significant difference between those 2 arms in favor of the targeted treatment.

Now, we have a medium observation period of 65 months, so over 5 years of follow-up for these patients, and all patients within the cohort have been now off study treatment for more than 4 years, meaning that the patients all received the fixed duration treatment and didn't receive CLL-specific treatment afterwards within the study. And, therefore, this allows us to now understand how the long-term outcome of these patients after a long period where they didn't receive any study treatment anymore. And therefore, this is the main goal of this long-term observation.

What was the design of the study?

Othman Al-Sawaf, MD: So, the main aim of the study was to compare the progression-free survival between the 2 arms. So, it was powered and designed to detect differences in the progression-free survival as defined by either a disease progression or a death of any cause. And therefore, in both arms patients had to have previously untreated CLL and also coexisting conditions, which was defined by a CIRS above 6 points. So, a community fitness rating scale of more than 6 points, which generally suggests high levels of clinically relevant coexisting conditions and/or an impaired renal function of creatinine clearance below 70 mL/minute, which is also an indicator of unfitness, so to speak.

And in both arms, it was important that patients receive exactly the same treatment duration. So, in both arms, patients stopped treatment after 12 cycles and were subsequently followed up. And in addition, we have a lot of additional secondary endpoints and also some exploratory endpoints in which we, for instance, look at the overall survival and also the minimal residual disease and the longitudinal minimal residual disease dynamics. Safety and toxicity, of course, is a key secondary endpoint, but also exploratory biomarker analysis that we will also show at this meeting, correlating, for instance, the transcriptomic profiles of the CLL cells before treatment and also at relapse in order to ultimately better understand how this treatment with targeted agents works in the setting of treatment naïve CLL.

What is the current follow-up and what do the progression-free survival data show?

Othman Al-Sawaf, MD: So, the current follow-up is 65 months. The median observation time is 65 months, and we do see now that the 5-year progression-free survival of the patients is approximately 63% compared to patients who receive chemotherapy, where the 5-year PFS was just 27%. So, we still don't have a median PFS with venetoclax–obinutuzumab. We're still continuing to follow up on the patients, but this clearly shows that even though the patients are now without any study treatment for more than 4 years, the vast majority of patients remain without a PFS event, really highlighting that the fixed duration approach is feasible in this group of patients.