Real World Comparison of Bruton Tyrosine Kinase Inhibitors and Venetoclax in Patients Diagnosed with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Abstract

Introduction Bruton tyrosine kinase inhibitors (BTKi's) including ibrutinib and acalabrutinib and the B-cell leukemia/lymphoma-2 inhibitor (BCL-2i) venetoclax have demonstrated favorable efficacy in the front-line and relapsed/refractory settings and are now approved standards of care for patients (pts) with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). While these novel agents have been favorably compared to chlorambucil-based therapy and other chemoimmunotherapy (CIT) combinations, direct comparisons between BTKi and BCL-2i have not been conducted in any line of therapy. As ongoing clinical studies are years away from providing data on these comparisons, we conducted a real-world analysis to evaluate clinical outcomes of comparable pts with CLL/SLL who received either BTKi monotherapy (mono) or BCL-2i + CD20 in first or second lines (1L, 2L) in the United States. Methods We conducted a retrospective cohort study using de-identified pt records retrieved from the Flatiron Health Enhanced Database (EDM) from 8/1/2014 to 2/28/2022. Adult pts were included if they had a confirmed CLL/SLL diagnosis (ICD-10: C91.1x, C83.0X), received BTKi mono or BCL-2i + CD20 monoclonal antibody (mAb), and had two or more clinical encounters in the study period. Index date was defined as the first date of initiation of either BTKi or BCL-2i treatment (tx). Pts were followed to the earliest of end of clinical activity, death, or end of data availability (2/28/2022). Time-to-next-treatment (TTNT) was used to compare the clinical performance of BTKi vs. BCL-2i and was defined as the current treatment's index date to the initiation of the next line of therapy (LOT) or death. BTKi was compared to BCL-2i + obinutuzumab (O) in the 1L and to BCL-2i + any CD20 mAb in the 2L. Propensity Score Matching (PSM) was used to improve the comparability between the tx cohorts using age, gender, race, Rai stage, time from diagnosis to tx, del (17p) / del (11q), IGHV mutational status, ECOG status, total number of lines received in study period, and prior novel agent exposure. Every BCL-2i pt was matched with two BTKi pts. Unmatched pts in the BTKi cohort were excluded. Separate descriptive and Kaplan-Meier (KM) analyses were performed for 1L and 2L pts. Results A total of 5,226 pts met the inclusion criteria and were treated in the 1L (n=3,676) and 2L (n=1772) settings. In the 1L, 92.4% (n=3,397) received BTKi mono and 6.7% (n=246) received BCL-2i + O. In the 2L, 84.4% (n=1,496) received BTKi mono and 15.6% (n=276) received BCL-2i + CD20 mAb. After applying PSM, the two cohorts were well balanced on all selected matched baseline characteristics in 1L (n=738) and 2L (n=838). (Table 1) In the 1L, the mean age across cohorts was 66.0 years, and 26.8% were female. In the 2L, the mean age across the cohorts was 69.4 years, 32.9% was female, and 32.6% of the pts had prior novel agents (Table 1). The median TTNT was not reached (NR) for the BTKi or BCL-2i cohorts in 1L or 2L. In the 1L, the mean (95% CI) proportion of pts remaining on tx or in tx free observation at 24 mos was 95.6% (92.8%, 97.3%) for the BTKi cohort and 92.7% (94.8%, 96.6%) for the BCL-2i + O cohort. For the 2L, the mean (95% CI) proportion of pts remaining on tx or in tx free observation at 24 mos was 84.9% (81.0%, 88.1%) for the BTKi cohort and 80.4% (73.6%, 85.6%) for the BCL-2i +CD20 cohort (Figure 1). Overall, the BTKi cohort had significantly longer TTNT than that of BCL-2i cohort in 2L. The difference in TTNT was not statistically significant in 1L. Conclusion Findings from this study showed that BTKi mono delays pts’ TTNT compared to BCL-2i + CD20 mAb in the 2L setting with a trend toward longer TTNT in the 1L setting that did not reach statistical significance. For the first time and in the largest dataset described to date, this study provides evidence that when considering the choice of BTKi vs. venetoclax-based therapy in 2L, clinical outcomes may favor selection of BTKi therapy. This result has immediate implications for tx selection in current clinical practice, may serve to inform the results of ongoing randomized studies and provides insight for future clinical trial design. Future studies will include longer pt follow-up, additional pts added to the dataset, assessment of discontinuation reasons for each class of therapy and assessment of TTNT stratified by key molecular / genetic prognostic factors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal