Treatment Patterns and Attitudes Among US-Based Physicians in Using BTK Inhibitors to Treat Relapsed/Refractory CLL and MCL
Authors: Topping Ryan P. , Quill Timothy A. , Awan Farrukh T. , Cohen Jonathon B. 
Published: December 2024

Background: The clinical management of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) continues to evolve. FDA-approved BTK inhibitors (BTKis), including the covalent BTKis acalabrutinib and zanubrutinib and the noncovalent BTKi pirtobrutinib, are recommended by guidelines and experts as options for first- and/or later-line treatment. However, with rapid advances in therapy, healthcare professionals (HCPs) may be challenged to remain current with optimal use of these agents. Here, we report treatment patterns and attitudes of US-based physicians in using BTKis to treat relapsed/refractory (R/R) CLL and MCL.
Methods: Physicians practicing in the US and actively treating patients with CLL and/or MCL were invited to participate in a survey on the management of patients with R/R CLL or MCL followed by a workshop in which participants could discuss cases from the survey with an expert/high-volume treater of CLL and MCL. Invitees were identified through a database of HCPs with an interest in CME on hematologic malignancies. Respondents to the invitation were vetted for eligibility based on NPI numbers and enrolled in the study on a first-come-first-served basis and offered an honorarium for their participation. Data from survey responses and anecdotes from workshop discussions were analyzed to determine treatment trends in the management of R/R CLL and MCL, with a focus on BTKi therapy.
Results: Among the 59 US-based physicians participating in this study from October 2023 to April 2024, 66% reported practicing at a community center and 44% in an academic setting. Most (75%) reported treating ≥11 patients with CLL and/or MCL per month.
Data from the survey showed that for a patient with CLL with mutated TP53/unmutated IGHV/del11q and relapse after first-line venetoclax plus obinutuzumab, most participants recommended zanubrutinib (55%) or acalabrutinib ± obinutuzumab (34%). In a patient with CLL with the above higher-risk features and an acquired BTK C481 mutation after relapse with both venetoclax-based therapy and a covalent BTKi, most participants (80%) recommended pirtobrutinib. Continuing with this patient, most participants recommended lisocabtagene maraleucel in the fourth-line setting after relapse with pirtobrutinib (70%). In the workshops, the most frequently asked questions surrounding R/R CLL centered on when to use an anti-CD20 antibody with acalabrutinib, factors impacting choice of acalabrutinib or zanubrutinib, resistance testing, utility of MRD testing, and best practices in transitioning to pirtobrutinib.
For R/R MCL, preferred treatment for relapsed disease after induction R-CHOP/R-AraC and consolidation autologous stem cell transplant was evenly split between acalabrutinib (46%) and zanubrutinib (39%). For a patient who experienced problematic diarrhea and bleeding/bruising with a covalent BTKi and wished to discontinue therapy, the most common recommendations were distributed between continuation of the covalent BTKi (25%), switch to pirtobrutinib (33%), and observation (34%).
For adverse event management, most participants (70%) recommended dose reduction for a case patient who started a covalent BTK inhibitor and experienced progressive joint aches with associated decline in quality of life consistent with guideline and expert recommendations. However, there was disagreement among participants in how to treat MCL in a case of a covalent BTKi hold for atrial fibrillation that was subsequently resolved, with participants split among strategies that included resuming the BTKi with counseling (29%), resuming the BTKi at a reduced dose (14%), transitioning to another BTKi (30%), or observation (16%). In the workshops, frequently asked questions focused on optimal use of BTKis in patients with thrombocytopenia and hypertension risk with available BTKis.
Conclusions: These data suggest that many US-based physicians who manage patients with R/R CLL and MCL provide therapy in line with expert and guideline recommendations. However, areas of disagreement and uncertainty exist, including scenarios of therapy transitions in the presence of comorbidities or adverse events, indicating ongoing educational needs.