First-Line Treatment of Older Patients with CLL: A New Approach in the Chemo-Free Era

SIMPLE SUMMARY: The modern treatment of chronic lymphocytic leukemia (CLL) has dramatically changed thanks to the development of effective mechanism-based drugs, which have proven to be superior to chemoimmunotherapy in all age groups. Because the choice of treatment for older patients largely depends on fitness status rather than chronological age, we aimed to discuss and put into perspective (i) the definition of an older patient, (ii) the efficacy of targeted agents in this patient population, and (iii) the cost-effectiveness of targeted therapy in high-income countries. ABSTRACT: Bruton tyrosine kinase inhibitors (BTKi) and the BCL2 inhibitor venetoclax, with or without the anti-CD20 monoclonal antibody Obinutuzumab, represent the preferred options for the first-line therapy of CLL because they are more effective and may improve quality of life. However, patient inclusion criteria are heterogeneous across trials designed for older patients, and the identification of CLL-specific parameters identifying unfit patients at risk of developing drug-specific adverse events is required to guide treatment choice. Due to inclusion/exclusion criteria in trials, higher discontinuation rates with BTKi were reported in real-world studies, and registry analyses provided useful information on factors predicting earlier discontinuation in a real-world setting. Though targeted agents were shown to be cost-effective treatments in high-income countries, the out-of-pocket expenses may limit accessibility to these drugs, and the overall expenditure for new drugs in CLL is projected to increase substantially, posing an issue for sustainability. This being said, the choice of a finite-duration treatment based on venetoclax-containing regimens or treatment until progression with BTKi is today possible in high-income countries, and the therapy choice drivers are represented by coexisting medical conditions rather than age, patient expectations, logistics, and sustainability.