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Sanjal Desai, MD, expands on the safety, efficacy, and sequencing of BTK inhibitors and venetoclax-based regimens in chronic lymphocytic leukemia.
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.
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.
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.
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.
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.
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.
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