Expanding CLL Treatment Arsenal Raises New Questions on Sequencing and Resistance

The October 2026 FDA approval of pirtobrutinib (Jaypirca) for adult patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma without a known 17p deletion further broadens an expanding set of treatment options in this setting and raises new questions for the field, according to Mary Ann Anderson, MBBS, FRACP, FRCPA, PhD.¹

In an exclusive interview with OncLive®, Anderson addressed some of the most pressing questions in CLL, along with highlighting key trials such as the phase 3 CLL17 study (NCT04608318). CLL17 randomly assigned patients with untreated CLL to receive either continuous ibrutinib (Imbruvica) alone or one of 2 time-limited regimens: venetoclax (Venclexta) plus obinutuzumab (Gazyva), or ibrutinib plus venetoclax.²

Anderson also discussed novel treatments such as BTK degraders and explained how the choice of BTK inhibitor partner may influence resistance to BCL2 inhibitors such as venetoclax.

Anderson is a hematologist at Royal Melbourne Hospital and Peter MacCallum Cancer Centre and a clinician scientist at the Walter and Eliza Hall Institute of Medical Research, in Melbourne, Australia.

OncLive: Where does the current frontline CLL treatment landscape stand? What should your colleagues know?

Anderson: With the emergence of so many safe and effective treatment options, we now have almost more questions than answers. Should we go with a continuous approach or a time-limited approach? If you go with a continuous approach, do you partner your BTK inhibitor with a monoclonal antibody? If you go with a time-limited approach, should you partner [the BCL2 inhibitor] with a monoclonal antibody or a BTK inhibitor? Should you use a triplet or a doublet?

If we're going with a continuous approach, do we use a fixed-duration approach or a minimal residual disease (MRD)–guided approach? Then, when it comes to second- and third-line treatment decisions, how do we optimally sequence? Thinking about these questions in the context of the individual in front of you can help ground those decisions. It isn't going to be one-size-fits-all; it's a tailored discussion between you and your patient about the right treatment option.

How can the CLL field best answer the remaining questions about treatment sequencing?

It's a tricky question, because a lot of the key questions [surround] which BCL2 inhibitor we should use going forward, as well as which BTK inhibitor we should use. We're unlikely to get truly randomized phase 3 data to help make these decisions, because those clinical trials are going to be hard to do. Collaborative group studies to tease out some of these real-world questions are going to be increasingly important.

One notable study is the CLL17 trial, which goes to the heart of these questions. It's asking whether we should use continuous BTK inhibition or BCL2 inhibitor–based finite treatment for our patients. That study is still maturing, but the initial readouts at about 3 years look like it doesn't matter. Both options result in equally good progression-free survival, even in patients with challenging genetic aberrancy. More of these kinds of studies to answer real-world questions are going to become increasingly important.

Do resistance mechanisms to venetoclax differ based on the BTK inhibitor used as a partner?

In terms of the differential patterns of resistance you might see with different BTK [inhibitor] partners for venetoclax, there are little data to help us understand this. What I would say is that on-target BCL2-related resistance mechanisms are rare when patients relapse after a period of time off a BCL2 inhibitor. The data we have for on-target resistance mechanisms are largely from early-phase clinical trials, where venetoclax was used as continuous therapy. In that setting, it's clear that patients develop resistance via a number of mechanisms, both on-target mutations in the BCL2 gene and through upregulation of other BCL2 family members.

The microenvironment is a critical part of that resistance, and there are probably mechanisms we haven't yet elucidated for why patients develop disease that relapses after an MRD-negative complete response from a time-limited regimen. We don't know; it is likely that MRD is an imperfect measure of disease, and that there is probably residual CLL that hasn't been mopped up by frontline treatment. There are ongoing studies in the frontline space after venetoclax-based approaches, using things like bispecific [antibodies] to try to consolidate these remissions. Whether that plays out as longer-term remissions or potentially functional cures in some patients is yet to be understood.

What emerging drug classes are you watching for future CLL treatment?

As we go forward, the exciting developments are likely to be in the BTK degrader space. Data coming out suggest that this group of drugs is efficacious in patients with highly relapsed disease. Another class of drugs to keep an eye on are bispecific [antibodies], which have emerging data in the field. Things are going to get more complex rather than less as we go forward, but it's an exciting time to work in [CLL].

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. FDA approves pirtobrutinib for previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. October 2, 2026. Accessed November 10, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pirtobrutinib-previously-untreated-chronic-lymphocytic-leukemia-or-small-lymphocytic
2. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. 2026;394(11):1084-1096. doi:10.1056/NEJMoa2515458