Site Editor
Jeremy S. Abramson, MD, MMSc
Jeremy S. Abramson, MD, MMSc
Posted: Thursday, March 10, 2022
Several novel therapies are available for chronic lymphocytic leukemia (CLL); thus far, however, no head-to-head, randomized, controlled trials have directly compared two effective classes of agents: Bruton’s tyrosine kinase (BTK) and B-cell lymphoma (BCL2) inhibitors. In a point-counterpoint discussion published in Blood Advances, Elizabeth A. Brem, MD, and Susan O’Brien, MD, of the University of California, Irvine, argued for the preferential first-line use of BTK inhibitors; John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre, Melbourne, Australia, endorsed BCL2 inhibitors as initial treatment.
The Case for BTK Inhibitors
BTK inhibitors are an efficacious and tolerable choice for most patients, according to Drs. Brem and O’Brien. “We now have over 6 years of follow-up from large, randomized phase [III] experiences with ibrutinib, demonstrating long-term efficacy in all subgroups,” they explained. The ALLIANCE A041202 and ELEVATE-TN trials showed that ibrutinib and acalabrutinib, respectively, improved 2-year progression-free survival compared with chemoimmunotherapy.
Drs. Brem and O’Brien also emphasized that patients with 17p-deleted or TP53-mutated disease may particularly benefit from the use of BTK inhibitor–based therapy, and that it may improve progression-free survival for patients with IgVH-unmutated disease. In the era of COVID-19 infection, observational data suggest that treatment with ibrutinib may protect against severe pulmonary inflammation in infected patients as well.
Although significant toxicities emerged with the use of BTK inhibitors, including atrial arrhythmia and bleeding, the investigators contend that there is now long-term experience with toxicity management. These toxicities appear to be less frequent with next-generation BTK inhibitors such as acalabrutinib and zanubrutinib, which boast increased selectivity; fewer cases of atrial arrhythmia have been reported in studies of these agents.
“BTK inhibitors are effective, tolerable oral agents that can be used without anti-CD20 therapy and tumor-lysis syndrome monitoring, making them the preferred choice for many patients requiring upfront therapy for CLL,” concluded the authors.
The Case for BCL2 Inhibitors
Because superior efficacy has not been established for either class of agents due to the lack of head-to-head trials, the considerations for a first-line agent should include tolerability, long-term toxicity, cost, and options for effective subsequent treatments, explained Dr. Seymour. He noted that the “widespread application” of continuous BTK inhibitor therapy with ibrutinib raises several concerning issues. The ibrutinib cessation rate due to toxicity ranged from 15% to 30% at 3 to 5 years of treatment in prospective clinical trials but is likely much higher outside of the carefully selected patient populations in studies.
Atrial fibrillation is another issue that can occur in up to 15% of patients in the first 3 to 5 years of treatment with ibrutinib. “Atrial fibrillation is inconvenient and creates management complexities...,,” stated Dr. Seymour. Because the median duration of drug exposure may exceed 10 years with continuous use of ibrutinib, the cumulative rates of these cardiovascular events will increase over time.
The personal and societal costs associated with widespread use of continuous BTK inhibitor therapy cannot be ignored as well, Dr. Seymour noted. Finally, the retention of venetoclax sensitivity at disease recurrence after time-limited therapy may allow for retreatment with reattainment of disease control.
Disclosure: For a full list of authors’ disclosures, visit ashpublications.org (BTKi) and ashpublications.org (BCL2i).
