The treatment landscape for chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) is rapidly evolving, with Bruton tyrosine kinase (BTK) inhibitors playing an increasingly significant role. A recent Frontline Forum brought together clinicians to discuss the latest advances and challenges in using these agents across different lymphoma subtypes.
CLL Management: Balancing Efficacy and Tolerability
In CLL, the National Comprehensive Cancer Network (NCCN) guidelines have shifted towards providing clinicians with more treatment options. While BTK inhibitor monotherapy offers a long-term approach with slow disease burden reduction, venetoclax plus obinutuzumab provides a time-limited strategy for deeper remission. However, BTK inhibitors are more widely used in the United States.
Data from the phase 3 RESONATE-2 trial suggest a sustained survival benefit with continuous ibrutinib therapy. However, long-term ibrutinib use can lead to adverse events like atrial fibrillation, prompting consideration of newer agents like acalabrutinib and zanubrutinib, which may offer improved tolerability. Some experts are dose-reducing ibrutinib to mitigate AEs and avoid switching over to second-generation BTK inhibitors.
The phase 3 ELEVATE-RR trial demonstrated comparable progression-free survival (PFS) between acalabrutinib and ibrutinib in relapsed/refractory CLL, while the phase 3 ALPINE trial showed superior PFS with zanubrutinib compared to ibrutinib in the same setting. Specifically, the PFS rates in the overall population were 64.9% in the zanubrutinib arm vs 54.8% in the ibrutinib arm. For those with del(17p) TP53 mutations, the PFS rates were 58.6% vs 41.3%.
Follicular Lymphoma: Expanding Treatment Options
For follicular lymphoma, treatment decisions are often based on tumor burden. While bendamustine plus rituximab remains a common first-line option, lenalidomide plus rituximab and tazemetostat are also considered, especially in later lines of therapy. The potential for bispecific antibodies to reshape the second-line treatment landscape is also anticipated.
The phase 2 ROSEWOOD trial evaluated zanubrutinib plus obinutuzumab versus obinutuzumab alone in patients with relapsed/refractory follicular lymphoma who had received two or more prior lines of therapy. The combination arm achieved a significantly higher overall response rate (ORR) of 69% (95% CI, 61%-76%) compared to 46% (95% CI, 34%-58%) in the monotherapy arm (P = .0012). This data supported the FDA's accelerated approval of zanubrutinib for this indication.
Mantle Cell Lymphoma: Towards Chemotherapy-Free Regimens
In MCL, there's a growing movement towards chemotherapy-free regimens, with BTK inhibitors playing a central role. Data from the phase 3 TRIANGLE trial suggest that maintenance therapy after BTK inhibitor treatment post-transplant improves outcomes. However, real-world data indicate that BTK inhibitor maintenance may yield similar outcomes to transplant alone.
When managing relapsed MCL, factors such as relapse type (high-risk, disseminated, or localized) guide treatment decisions. Acalabrutinib and zanubrutinib are available options for patients who have progressed on prior covalent BTK inhibitors. The importance of considering TP53 mutations and the tumor microenvironment in MCL treatment strategies was also emphasized.
Addressing Treatment-Related Challenges
Experts also discussed strategies for managing treatment-related adverse events and optimizing patient care. Vaccination prior to initiating treatment with CD20 antibodies and BTK inhibitors is crucial due to blunted vaccine responses. For atrial fibrillation observed with ibrutinib, cardio-oncology consultation and anticoagulation may be necessary. Switching to acalabrutinib or zanubrutinib, or using a venetoclax-based regimen, can also be considered.
