Dr Lamanna on the Use of Novel Agents Following Progression in CLL

Nicole Lamanna, MD, hematologist/oncologist, associate clinical professor, medicine, Hematologic Malignancies Section, Hematology/Oncology Division, Columbia University, Herbert Irving Comprehensive Cancer Center, discusses how the use of novel agents could address resistance associated with current treatment options for patients with chronic lymphocytic leukemia (CLL).

The primary focus of therapies for CLL has revolved around covalent BTK inhibitors, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), Lamanna begins. As patients undergo prolonged treatment with these therapies, Lamanna states that oncologists like herself observe the emergence of resistance mutations, primarily at the BTK C481 binding site domain. Additionally, there is a smaller occurrence of non-BTK C481 mutations, specifically gatekeeper mutations and kinase impaired mutations; although these are infrequent, they warrant vigilant monitoring, she explains. The impact of these resistance mutations on the future sequencing of BTK inhibitors remains to be seen, Lamanna notes.

In cases where patients develop progressive disease or resistance mutations to covalent BTK inhibitors, the conventional approach involves transitioning to a venetoclax (Venclexta)–based regimen, Lamanna says. Venetoclax is a BCL2 inhibitor with a time-limited treatment strategy, unlike the continuous therapy of covalent BTK inhibitors, she expands. However, some patients also experience progression on venetoclax-based regimens, prompting the exploration of newer agents for this patient population. Noncovalent BTK inhibitors, such as pirtobrutinib (Jaypirca) and nemtabrutinib (ARQ-53), are under investigation in this context, she emphasizes. Although pirtobrutinib is currently approved for patients with mantle cell lymphoma in the relapsed/refractory setting, its approval for patients with CLL is pending, she says. Encouraging data from the phase 1/2 BRUIN study (NCT03740520) have led to the inclusion of pirtobrutinib in the National Comprehensive Cancer Network Guidelines. Consequently, for patients progressing on covalent BTK inhibitors or venetoclax-based therapy, considering pirtobrutinib in this setting is a viable option, Lamanna says.

Novel agents with unique mechanisms of action are also being explored in clinical trials, although they have not yet received approval for patients with CLL, she continues. These include CAR T-cell therapies, BTK degraders, and bispecific monoclonal antibodies, Lamanna explains. These clinical trials aim to address the needs of patients developing resistance mutations to covalent BTK inhibitors or those refractory to venetoclax-based therapy, she concludes.