OBJECTIVES: To identify overall survival (OS) prognostic factors in patients with heavily pretreated chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) and to identify surrogate endpoint analyses considering OS or progression-free survival (PFS) as final endpoints in any line of therapy.
METHODS: A systematic literature review was conducted to a prespecified protocol. Electronic databases with no date or language limits and grey literature were searched. Included studies were assessed according to Joanna Briggs Institute critical appraisal tools. Significant relationship was defined as having P<0.05 in all analyses performed across studies.
RESULTS: Of 3395 publications screened, 24 reported prognostic factors for heavily pretreated CLL/SLL and 29 reported surrogate analyses. Older age, fludarabine use or alkylator-refractory disease, ≥3 prior therapies, bulky disease, and 17p deletion were independently associated with shorter OS in the heavily pretreated CLL/SLL population. Minimal residual disease (MRD) negativity was associated with longer PFS (9 of 10 studies, P<0.05) and OS (11 of 12 studies, P<0.05) in patients on any line of therapy. Multiple publications reported response to be associated with OS (10 of 11 studies, P<0.05) and PFS (all 6 studies, P<0.05). Other surrogate endpoints reported were PFS as a surrogate for OS (1 study, P<0.05) and disease progression (2 of 3 studies, P<0.05). Only 1 publication used metaregression to perform surrogate endpoint analysis on treatment effects, with increased MRD response between treatments associated with improved PFS, R2=0.44 (Dimier et al, 2018).
CONCLUSIONS: The most common surrogate endpoint was response, which was associated with OS and PFS. Despite a large body of literature, few publications reported analyses of prognostic factors or surrogate endpoints, particularly in heavily pretreated patients, or used the latest bivariate meta-analysis methods.
