Diagnosis and Management of Chronic Lymphocytic Leukemia with TP53 Loss of Function in the Novel Agent Era

TP53 loss-of-function (TP53-LoF) remains the single most important prognostic factor in chronic lymphocytic leukemia (CLL). Comprehensive assessment for TP53-LoF requires testing for both gene deletion and mutation. Historically, patients with TP53-LoF CLL have had poor outcomes and experienced short survival when treated with chemoimmunotherapy. In the novel agent era, multiple studies have demonstrated the effectiveness of continuous covalent BTK inhibitor (cBTKi) therapy, especially in the frontline setting, with a median progression-free survival (PFS) of approximately 7 years. Continuous cBTKi is therefore the de-facto standard for current management of TP53-LoF CLL. In contrast, fixed-duration regimens combining venetoclax with either obinutuzumab or cBTKi have shown slower response kinetics with longer time to undetectable minimal residual disease (uMRD) status, and reduced PFS, in patients with TP53-LoF CLL. Although early data from fixed-duration regimen studies indicate that most patients respond to retreatment, specific data for the TP53-LoF subset have not been reported. Therefore, the application of fixed-duration regimens for treatment of TP53-LoF CLL requires careful deliberation on the risks vs benefits of long-term cBTKi therapy, and acceptance of the uncertainty around the lack of granular retreatment outcomes. Multiple fixed-duration studies have shown that uMRD is a key endpoint in patients with TP53-LoF CLL. In this respect, clinical trials examining consolidation strategies in patients with detectable MRD, or in those with high-risk genomics, may be especially impactful in patients with TP53-LoF CLL.