1110 - Systematic literature review (SLR) of treatments and outcomes in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with Bruton tyrosine kinase inhibitors (BTKi) and venetoclax

Introduction: CLL/SLL remains incurable, despite the introduction of targeted agents such as BTKi and the B-cell lymphoma 2 inhibitor (BCL2i) venetoclax. Patients with R/R CLL/SLL require multiple lines of therapy, and outcomes are poor in these patients. Thus, an SLR was conducted to understand the efficacy of treatments for patients with R/R CLL/SLL who have failed ≥2 prior lines of therapy (i.e., third-line or later [3L+] R/R CLL/SLL), especially those previously treated with a BTKi and venetoclax.

Methods: Searches of the following sources were conducted: bibliographic databases (Medline, Embase, Cochrane Library) from inception to September 2022; trial registries; regulatory/health technology assessment agency websites from inception to October 2022; and conference proceedings from January 2020 to February 2023. Moreover, bibliographies of included SLRs were hand searched. Identified records were screened using the Population, Intervention, Comparator, Outcome, and Study design framework. Selection criteria targeted English language publications, reporting on studies of phase 2+ or observational study design, investigating all available treatments for adult patients with R/R CLL/SLL. Data extracted included study description, treatment information, baseline patient and disease characteristics, and efficacy outcomes. Where available, reported efficacy outcomes were classified according to either individual pharmacologic classes or class groupings, such as conventional systemic therapies (e.g., BTKi, BCL2i/venetoclax, phosphoinositide 3-kinase inhibitors [PI3Ki], chemoimmunotherapy, or combinations of the aforementioned), allogeneic stem cell transplantation (alloSCT), noncovalent BTKi, and chimeric antigen receptor (CAR) T cell therapy.

Results: Of the 643 studies included in the SLR, 41 trials and 25 observational studies reported outcomes data specifically in patients with 3L+ R/R CLL/SLL. Of those, only 6 (2 trials and 4 observational studies) reported data in patients previously treated with BTKi and venetoclax. The 2 trials were phase 1/2 and investigated outcomes with noncovalent BTKi (nemtabrutinib and pirtobrutinib) as 3L+ treatments (Table 1). The complete response (CR) rate was 0% in both trials, whereas objective response rate (ORR) was 58% and 79%, and median progression-free survival (PFS) was 10.1 and 16.8 months, for nemtabrutinib and pirtobrutinib, respectively. Neither trial reported overall survival (OS) data. Across the 4 observational studies (Table 2) where efficacy outcomes were reported for conventional systemic therapies, the CR rate ranged from 5.9% for PI3Ki therapy to 10.0% for BTKi, ORR ranged from 31.8% for chemoimmunotherapy to 53.4% for BTKi, median PFS ranged from 3 months for chemoimmunotherapy to 12 months for BTKi, and median OS ranged from 3.6 to 16.6 months for any conventional systemic therapy. For observational studies reporting data for alloSCT, ORR was 76.5%, and median PFS was 11 months; for noncovalent BTKi, ORR was 75.0%, and median PFS was not reached at a median follow-up of 9 months; for CAR T cell therapy, CR rate was 33.3%, ORR was 66.6%–85.7%, and median PFS was 4–9 months. Among the 6 included studies that reported on patients previously treated with BTKi and venetoclax, duration of response (DOR) was only reported in the nemtabrutinib trial, where the medium DOR was 8.5 months (95% confidence interval, 2.7–not estimable).

Conclusions: There remains a high unmet medical need for patients with 3L+ R/R CLL/SLL previously treated with BTKi and venetoclax, with poor outcomes associated with conventional systemic therapies. Novel therapies such as CAR T cell therapy and noncovalent BTKi may provide better efficacy outcomes; however, no CR was observed with noncovalent BTKi in the included trials.