Sequencing and combination of current small-molecule inhibitors for chronic lymphocytic leukemia: Where is the evidence?

Small-molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL), a landscape once dominated by chemoimmunotherapy (i.e., an anti-CD20 monoclonal antibody in combination with systemic chemotherapy) in fit and unfit individuals. Key challenges include the management of refractory disease as well as the optimization of the therapy sequence. Decreased responsiveness has been observed with prolonged treatment, especially with Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase (PI3K) inhibitors which are given continuously, while venetoclax, an agent that targets dysregulations in intrinsic apoptosis signaling, has a fixed duration when combined with anti-CD20 monoclonal antibodies or BTK inhibitors. Combination therapy aims to synergistically target different oncogenic signaling pathways to abrogate the proliferation of resistant clones and thereby allows for fixed-duration treatments. An advantage of fixed-duration therapy is the potential to decrease financial and drug-induced toxicities. Sequencing of therapies is important to individualize treatment decisions based on factors such as age, comorbidities, tolerability, and patient preferences. However, to date, there are limited data to guide the rational sequencing or combination of these therapies, since conventional chemoimmunotherapy or chemotherapy regimens were used as comparators against these small-molecule inhibitors in trials that led to their regulatory approvals. In this article, we examined and evaluated the current evidence for sequencing versus the combination of small-molecule inhibitors for CLL by conducting comprehensive searches of the United States National Library of Medicine PubMed database, key meeting abstracts, and clinical practice guidelines. We also summarized findings from expert opinions to elucidate best practices for clinical scenarios with limited evidence to guide treatment selection.