Desai Details Efforts Exploring Treatment Strategies in CLL Post–BTK Inhibitor Progression

In an interview with OncLive^®, Sanjal Desai, MD, discussed the feasibility of venetoclax (Venclexta) rechallenge in patients with chronic lymphocytic leukemia (CLL) who progressed on prior covalent BTK inhibitors; highlighted the significant genetic heterogeneity of the mutational landscape post–BTK inhibitor progression; and underscored the necessity for further research to determine the role of venetoclax after noncovalent BTK inhibition has failed, as well as to optimize treatment strategies for those with double-refractory disease.

“We have a lot of agents available for CLL, which is great [and] wasn’t the case before 2010,” said Desai, who added, “I look forward to more breakthroughs.” Desai is a medical oncologist at Mayo Clinic and an assistant professor of medicine in the Division of Hematology, Oncology and Transplantation at the University of Minnesota in Rochester. In another article, Desai explained how genetic information and patient factors influence sequencing decisions in the frontline setting and beyond.

OncLive: What do current data indicate about the feasibility of venetoclax rechallenge after a patient with CLL experiences disease progression on a prior BTK inhibitor?

Desai: [We have seen] data from retrospective studies, and I was able to show that in my presentation, as well. The findings are encouraging. [In] patients who have [received] venetoclax as a time-limited therapy and [achieved] durable remission, [which] is typically defined as 1 to 2 years, venetoclax rechallenge can lead to encouraging response rates of up to 70% and durable remission of approximately 2 years. I would consider venetoclax rechallenge for that kind of patient.

It is important to test for genetics at the time. If [a patient displays] a TP53 mutation or deletion that has evolved at the time, a BTK inhibitor might be a better choice. If a patient has progressed on venetoclax therapy or [experienced] a duration of remission that is less than a year, venetoclax rechallenge is probably not the best idea.

How would you describe the mutational landscape for CLL following BTK inhibitor progression?

[There were presentations at the 2023 ASH Annual Meeting] on the mutational landscape of patients who [progressed on] covalent BTK inhibitors. We see mutations in that cohort with varying frequencies in the BTK pathway, or BCL-2 gamma pathway, or TP53 mutations, etc. After [progression on] a BTK inhibitor, the disease is quite heterogenous genetically. [This research] calls for investigations of those novel agents to dive into specific mutations.

What information is needed to better elucidate the efficacy of venetoclax rechallenge post-progression on a noncovalent BTK inhibitor?

[Regarding] the use of venetoclax after [progression on] BTK inhibitors, we have good [retrospective] data showing that approximately two-thirds of patients who [progressed on a] BTK inhibitor respond to venetoclax and have a median progression-free survival [PFS] of approximately 2 years. That would make me choose venetoclax for patients who progress on [prior] BTK inhibitors. To my knowledge, we don’t have data yet on venetoclax’s efficacy in patients [who progressed on] noncovalent BTK inhibitors, such as pirtobrutinib [Jaypirca].

As I showed in my presentation, the mutational landscape of those patients is quite heterogeneous. We need more studies to [assess] the efficacy of a BCL-2 inhibitor in those patients. I’m inclined to choose venetoclax for a patient [who progressed on a] BTK inhibitor and who is venetoclax naive, because we have data on the efficacy of pirtobrutinib after [progression on] venetoclax, but not the other way around yet.

What are some remaining unmet needs in CLL and what research efforts are needed to address them?

We need more investigations on how to optimize treatment for patients who are double refractory, [or those who progress on a] covalent BTK inhibitor and venetoclax, because we see that pirtobrutinib works, but [the majority of] patients [have not] achieved a complete remission in that trial [according to the] present data. We need to optimize that dose. The median PFS was [approximately] 19 months, so there’s a lot of room for more optimization of treatment to improve outcomes in terms of PFS as well as response rates.

There’s also a lot of room for [research on novel combinations]. CAR T-cell therapy was recently approved for refractory patients, and it will be interesting to see how long-term durability of response is after [this modality], because most CLL treatments in the relapsed setting are continuous therapies. It will be nice to [see whether] the CAR T [administration], which is a one-time procedure, can lead to deeper responses. Those are some active investigations in CLL.