Genetic Information and Patient Factors Influence BTK Inhibitor Sequencing in Frontline CLL and Beyond

In addition to efficacy and safety data, patient preferences, genetic profiles, and comorbidities serve as key factors for informing frontline treatment decision-making in chronic lymphocytic leukemia (CLL), particularly regarding the choice between BTK inhibitors and venetoclax (Venclexta)-based therapy, according to Sanjal Desai, MD.

Desai added that although retrospective data and post-hoc analyses suggest a potential survival advantage with BTK inhibitors over venetoclax in TP53-aberrant CLL, future studies are still needed to confirm the optimal sequencing of these strategies.

“For the longest time [we only had] chemotherapy-based regimens [available in CLL]. Now we have been able to treat our patients for the most part with chemotherapy-free regimens, and chemotherapy has really taken a backseat,” said Desai, who is an assistant professor of medicine in the Division of Hematology, Oncology and Transplantation at the University of Minnesota in Rochester.

In an interview with OncLive^®, Desai discussed how genetic information can influence the choice between frontline therapies in CLL; expanded on the safety, efficacy, and optimal sequencing of covalent and noncovalent BTK inhibitors in this space; and discussed scenarios that would warrant switching patients to alternative covalent BTK inhibitors in the event of progression or treatment-related toxicities.

OncLive: How does genetic information inform treatment decision-making in frontline CLL?

Desai: The first [topic I discussed in my presentation] was whether genetics matter when you’re choosing between frontline agents and thinking about [treatment] sequencing. I showed some retrospective data as well as a post-hoc analysis from a clinical trial that suggested that BTK inhibitors might be more efficacious in TP53-mutant or -deleted CLL compared with venetoclax-based therapy. That can be a consideration when choosing between those 2 agents in the frontline. However, patients who [progress on] venetoclax can be salvaged effectively with BTK inhibitors in [subsequent] lines––I showed some retrospective data showing that. What we need future studies to [elucidate is whether] there is an overall survival advantage [using] 1 agent [before the] other in the frontline setting in TP53-mutant CLL.

What are the safety and efficacy profiles of acalabrutinib (Calquence) and zanubrutinib (Brukinsa) vs ibrutinib (Imbruvica) in CLL, and how do these profiles influence treatment sequencing in the frontline?

I also discussed data showing the favorable safety profile of acalabrutinib and zanubrutinib, from an anemia and bleeding standpoint, compared with ibrutinib, which was the first-in-class BTK inhibitor approved for CLL. [Additionally], some data show that zanubrutinib has superior efficacy compared with ibrutinib. In general, acalabrutinib and zanubrutinib [should be] considered [for use before ibrutinib] because of their favorable safety profiles.

Mainly for the frontline sequencing of therapy, especially for CLL that [does not harbor] TP53 mutations or deletions, the choice between different agents depends on patient preferences as well. Their preference between fixed-duration vs long-term therapy as well as patients’ comorbidity profiles. Those things come into play when we have multiple agents that are available.

Pirtobrutinib [Jaypirca] and other non-covalent BTK inhibitors will [enter the] current treatment paradigm [in later lines] because all the available data we have [are in] patients [who] have [progressed on] venetoclax and BTK inhibitors [and are considered] double refractory. CAR T[-cell therapy] will [have a role] in a similar space as well.

What data support the use of zanubrutinib over ibrutinib or acalabrutinib in treatment-naive or BTK inhibitor–naive patients with CLL?

Zanubrutinib is a covalent BTK inhibitor. There have been data showing its efficacy in the relapsed/refractory setting as well as the frontline. Some of the data I showed in my presentation compared zanubrutinib with ibrutinib. There was a noninferiority analysis which was positive, and then the superiority analysis for progression-free survival [PFS] that was positive as well. Zanubrutinib might have superior efficacy compared with ibrutinib in terms of PFS and a favorable safety profile. However, it is a covalent inhibitor, so it does not have a [role for] patients who [progress on] ibrutinib or acalabrutinib. I would probably favor zanubrutinib for [patients with] treatment-naive or BTK inhibitor–naive CLL. For them, it’s definitely a feasible option, [and in] older individuals atrial fibrillation [events] are frequently observed, so it helps to have a treatment option that doesn't increase the likelihood of atrial fibrillation.

As the latest addition to the treatment arsenal in CLL, when should the noncovalent BTK inhibitor pirtobrutinib be utilized for patients with pretreated CLL?

Pirtobrutinib is a noncovalent inhibitor, and the data we have currently [with this agent] are encouraging in patients who [progressed on] BTK inhibitors. [This includes] the subgroup of patients who have [progressed on] both venetoclax and BTK inhibitors. Also, it [seems] like pirtobrutinib [produced] responses [in this subgroup that were] similar to [those seen in] the entire cohort. For me, pirtobrutinib should be considered for patients who have progressed on covalent BTK inhibitors. Since venetoclax has good data in that space as well, I typically feel that we [should use] venetoclax for patients who [progress on] BTK inhibitors first, and reserve pirtobrutinib for patients who are double refractory at this point in time.

In which scenarios would you consider switching patients to an alternative covalent BTK inhibitor if they experience progression?

If patients have seen a covalent BTK inhibitor, and if the treatment [was] stopped [due to] toxicities that are specific to that inhibitor [that] could be less frequent with the other agents, such as treatment-resistant atrial fibrillation with ibrutinib, then I would switch to zanubrutinib or ibrutinib. That is because we have some data [indicating that] if covalent BTK inhibitors are stopped for toxicity, another covalent BTK inhibitor may still have good activity in that patient. That would be the situation [in which I would switch] from one covalent BTK inhibitor to another.