Presentation (CTI)

OBJECTIVES: The treatment landscape of chronic lymphocytic leukemia (CLL) continues to evolve with the introduction of BCL2-inhibitors (BCL2i), second-generation covalent BTK inhibitors (cBTKi), and non-covalent BTK inhibitors (ncBTKi). Simultaneously, implementation of EU Joint Clinical Assessment (JCA) and Medicare Drug Price Negotiation under the Inflation Reduction Act (IRA) has increased demand for timely evidence on emerging therapies, patient populations, and treatment pathways. We used a Real-Time AI-Assisted Living Systematic Literature Review (REAL-SLR) to characterize the development landscape in relapsed/refractory (R/R) CLL and identify emerging evidence needs relevant to HTA and payer decision-making.
METHODS: A PRISMA-compliant, continuously updated REAL-SLR was conducted in CLL. Interventional studies identified from publications and conference abstracts were mapped according to study design, population characteristics, treatment pathway, biomarker status, and intervention class. US/European regulatory documents and treatment guidelines supplemented evidence mapping. Studies evaluating novel therapies with publications from 2022 onward were included.
RESULTS: As of June 15, 2026, the REAL-SLR included 341 investigational studies, of which 212 (62%) evaluated R/R CLL. Thirty-six studies investigated emerging therapies, including BCL2 inhibitors, next-generation BTK inhibitors, BTK degraders, CAR-Ts, and bispecific antibodies. Sixty-one percent reported outcomes in patients previously exposed to cBTKi and/or BCL2i, while 19% evaluated del(17p)/TP53-mutated populations. Only two studies each evaluated double-class or triple-class exposed populations (BGB-16673, rocbrutinib), and three reported outcomes in patients with BTK mutations (BGB-16673, sonrotoclax, selinexor+ibrutinib). Overall and progression-free survival were reported in 33% and 64% of studies, respectively.
CONCLUSIONS: Living evidence monitoring demonstrated that therapeutic innovation in R/R CLL is concentrated in previously treated populations, while evidence remains limited for double-class exposed, triple-class exposed, and biomarker-defined subgroups. These findings highlight emerging evidence gaps that may influence comparator selection, value assessment, and evidence-generation strategies. Living literature monitoring may support identification of evolving treatment pathways and evidence requirements relevant to HTA, JCA, IRA, and payer decision-making.