Suchitra Sundaram, MD, discusses the assortment of therapies available in chronic lymphocytic leukemia and frontline approaches.
As the chronic lymphocytic leukemia (CLL) field introduces a plethora of treatment options, specific data and clinical trials are helping shape treatment regimens that showcase second-generation BTK inhibitors plus BCL2 inhibitors, according to Suchitra Sundaram, MD.
In an interview with OncLive®, Sundaram touched on numerous BTK inhibitors like ibrutinib (Imbruvica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), and pirtobrutinib (Jayprica). Sundaram dove into data that help make sense of all available options for patients with CLL and which combinations are optimal in the frontline. She specifically highlighted the phase 3 CLL17 (NCT04608318) trial and its data that are helping inform treatment selection in CLL regarding fixed-duration therapies and continuous BTK inhibitor treatment.1,2
“[With fixed-duration therapy], BTK inhibitors are typically administered…with a goal of achieving a deep remission, allowing a treatment-free interval. However, the optimal approach has not been established; this is where we saw some very interesting data from the CLL17 trial,” Sundaram said in the interview.
Sundaram is an assistant professor of medicine of hematology and medical oncology at the Tisch Cancer Institute at the Icahn School of Medicine in New York, New York.
This is a very exciting time to be a CLL practitioner because we have access to a lot of these novel therapies and a bunch of these combination therapies that are being studied in clinical trials. Notably, at the
Some other trials that are very interesting [evaluate] the role of pirtobrutinib in frontline CLL. We know that [pirtobrutinib] is an excellent, next-generation [noncovalent] BTK inhibitor in CLL, and to see its relevance in the frontline space has been of great interest to a lot of practitioners treating CLL. [Therefore,] the [phase 3] BRUIN-313 [NCT05023980] and BRUIN-314 [NCT05254743] trials in that space are extremely interesting.
There’s a lot of data with the second-generation BTK inhibitors in the last few years that we've been following. We’re especially interested in zanubrutinib vs ibrutinib, for example. That is one area that we did see some benefit for zanubrutinib over ibrutinib, and that would be some space that we want to keep following to see more data on progression-free survival [PFS] and maybe see if there's any [notable] overall survival data.
PFS is very relevant in this space. Regarding acalabrutinib vs ibrutinib in the long-term data, we didn't quite see a difference in terms of efficacy. However, it certainly would be interesting to follow [the adverse effect (AE) profile of each drug]. Furthermore, if there are head-to-head comparison trials of the 2 second-generation BTK inhibitors, [acalabrutinib and zanubrutinib], that would be very interesting as well.
Along the same space, pirtobrutinib, is an exciting drug that we were interested to see some frontline data now presented at ASH 2025. [Pirtobrutinib] is a BTK inhibitor that has few AEs and is well tolerated. [Thus,] in CLL with continuous therapy, what becomes important is: How are patients likely to stay on a certain drug long-term? Certainly, we know that there are AEs associated with ibrutinib that can lead to treatment discontinuations. Just based on the superior AE [profile] of pirtobrutinib, it's likely that more patients are going to stay on the drug. [Patients receiving pirtobrutinib long-term] might translate to better outcomes. I'm interested to know how that space looks in the years ahead to inform us more about the utility of [pirtobrutinib] in earlier lines of therapy.
If you look at the current treatment paradigm for CLL, they follow 2 treatment [paths]. There's continuous treatment with BTK inhibitors until disease progression, aimed at disease control, or there's fixed-duration regimens combining BCL2 inhibitors like venetoclax with an anti-CD20 antibody or BTK inhibitor.
[CLL17] is a prospective, randomized trial that looked at patients with untreated CLL, which is a large study that looked trial that compared continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab [Gazyva] and then also fixed-duration venetoclax plus ibrutinib. Granted, ibrutinib is likely not a drug that we use commonly these days with the second-generation drugs BTK inhibitors available. However, one can think that this data could be extrapolated with the second-generation BTK inhibitors well. The study was designed to test the noninferiority of the fixed-duration regimens vs ibrutinib alone in terms of PFS.
What was interesting was that the 3-year PFS [rate] was 81.1% in the venetoclax plus obinutuzumab arm, 79.4% in the venetoclax plus ibrutinib arm, and 81.1% in the ibrutinib monotherapy arm. These data established noninferiority of PFS across the groups, and what was interesting and will be interesting going forward to follow-up was the undetectable minimal residual disease [uMRD] rate. [uMRD in the CLL17 trial] is 10-4 in the peripheral blood, and it was achieved in 73.3% in patients who were treated with venetoclax plus obinutuzumab and 47.2% [for] venetoclax plus ibrutinib. These data just show that that with the venetoclax plus obinutuzumab regimen both in the peripheral blood and in the bone marrow, the remissions were deepest. Then [venetoclax plus obinutuzumab] was followed by venetoclax plus ibrutinib.
In general, one can infer so far that the fixed-duration approach tends to be noninferior in the general population of untreated CLL. However, I would be cautious to extrapolate this data to the TP53-mutated CLL field, which was only a small subset of the study population. Since the number of patients [with TP53-mutated CLL] is small and also the follow-up being limited, I would still elect to treat these patients with continuous BTK inhibitors, which we have the longest data for so far.
In terms of safety profile, which was a major concern with these regimens, infections continue to remain a challenge in CLL. [Infections] affected [approximately] 70% of patients on this trial. We have to be mindful that a lot of the recruitment happened during the COVID pandemic, and we do know that anti-CD20 antibodies are associated with an increased risk of infection. We'll just have to be mindful of these AEs. Cytopenias also were common with [venetoclax plus obinutuzumab], as compared with single-agent therapy. The known cardiovascular toxicities with regimens containing ibrutinib were also seen. Overall, I feel the AE profile with all the 3 arms [of CLL17] were similar to what we've seen with prior trials in our experience with these individual agents. This was pretty good data. Along the same lines, we do have
