A network meta-analysis and whole-exome analysis of chronic lymphocytic leukemia patients treated with ibrutinib and chlorambucil

Abstract

Abstract (project 1) Background Both ibrutinib and chlorambucil, used alone or in combination, have been used for first-line treatment for CLL. However, a comprehensive comparison among different CLL therapies, including ibrutinib or chlorambucil, is still lacking. In this study, we used network meta-analysis to estimate the effects of these therapies on clinical outcomes. Methods We did a network meta-analysis based on a systematic review comparing ibrutinib or chlorambucil against ibrutinib or chlorambucil combined with other medicines, other CLL treatments, placebo, or no treatment. Five databases were searched from inception up to Feb. 12, 2022. Only randomized controlled trials were included for analysis. The primary efficacy outcome was progression-free survival, and the primary safety outcome was based on adverse events. This study was registered with PROSPERO. Results A total of 6 eligible studies involving 1618 patients treated with six different treatment therapies were assessed. Compared with chlorambucil alone as reference therapy, both ibrutinib and ibrutinib combined therapies (ibrutinib plus ublituximab) significantly prolonged progression-free survival (HR 0.16, CI95% [0.04, 0.74]; HR 0.08, CI95% [0.01, 0.86], respectively). No significant difference in progression-free survival was found between chlorambucil and rituximab, or between ibrutinib and ibrunitib combined therapies. No significant difference in the safety outcome based on adverse events was found between chlorambucil, ibrutinib, ibrutinib plus rituximab, ibrutinib plus ublituximab, and rituximab alone. Conclusion Significant differences exist among ibrutinib, chlorambucil, and their combined therapies in terms of progression-free survival. Both ibrutinib and ibrutinib plus ublituximab might be considered over chlorambucil. Further randomized clinical trials directly comparing the interventions such as ibrutinib plus ublituximab versus chlorambucil alone should be designed to validate the results in our study. Abstract (project 2) Background Although ibrutinib has been approved for CLL initial treatment by the Food and Drug Administration and listed as the first-line therapy by the National Comprehensive Cancer Network (NCCN) guideline, clonal evolution of CLL under the treatment of ibrutinib is still understudied. Method We used the samples from ibrutinib and chlorambucil group in an open-label randomized clinical trial (NCT01724346) from 108 centers in 16 countries and recruited the watch-and-wait observational cohort at the study center of University Of California San Diego. The primary outcome of this study was response rate. Whole-exome sequencing was used for both the tumor and normal samples at baseline, 1 year, and 2 years after treatment initiation. Drivers were identified using MutSig2CV, and PhylogicNDT was used to analyze clonal evolution and dynamics. Results A total of 216 patients with a mean age of 69.7 years (SD 6.9) were included in this study. The overall response rate was 28.6% in the chlorambucil group, as compared with 76.7% in the ibrutinib group (p 0.001). There was a significant difference in the number of changing subclones across watch-and-wait group (6 changing subclones out of 84 subclones), chlorambucil group (13 changing subclones out of 64 subclones), and ibrutinib group (30 changing subclones out of 66 subclones) (p 0.001). In the ibrutinib cohort, the significantly mutated genes included NOTCH1, SF3B1, BCOR, NRAS, and BIRC3. BIRC3 mutation in the increasing subclone was significantly associated with the clinical outcome of stable disease (p = 0.013). Conclusion The subclonal diversity in CLL patients treated with ibrutinib changes more than with chlorambucil or watch-and-wait. NOTCH1, SF3B1, BCOR, NRAS, and BIRC3 are drivers in expanding subclones under ibrutinib therapy. BIRC3 mutations are significantly associated with clinical response in the CLL patients treated with ibrutinib.