| Sumario: | Simple Summary: Treatment of patients with mantle cell lymphoma is rapidly evolving, driven by several recent clinical trials showing that combining covalent Bruton's tyrosine kinase inhibitors with other therapies can lead to improved outcomes. Although these newer treatment approaches expand available options and offer greater flexibility, choosing the best therapy has become more complex. Optimal treatment selection increasingly requires a personalized approach that considers disease features, patient health and preferences, and local factors such as access to care. In this paper, we present three patient cases to illustrate how these factors influence decision-making and to highlight the practical considerations involved in selecting among standard and emerging first-line covalent Bruton's tyrosine kinase inhibitor-based combinations. First-line (1L) therapy for mantle cell lymphoma (MCL) continues to evolve rapidly, with several recent phase II and phase III trials consistently showing the activity of novel covalent Bruton's tyrosine kinase inhibitor (cBTKi) combinations. Historical treatment selection criteria such as patient age, fitness, and eligibility for autologous stem cell transplantation generally remain applicable for some, but not all, of these novel regimens. This potential for flexibility necessitates the consideration of additional factors during decision-making, such as MCL biology, patient risk tolerance, logistical and resource implications, and the impact on use of later-line options. This paper presents three illustrative patient cases to explore 1L therapy selection among these new and emerging cBTKi options. The realized and anticipated benefits, limitations, and challenges and persisting evidence gaps associated with these regimens are discussed.
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