Comparative Efficacy of Bruton Tyrosine Kinase Inhibitors in the Treatment of Relapsed/Refractory
Chronic Lymphocytic Leukemia: A Network Meta-Analysis
Mazyar Shadman*1, Jennifer R. Brown2, Leyla Mohseninejad3, Keri Yang4, Heather Burnett5, Binod
Neupane5, Rhys Williams4, Nicole Lamanna6, Susan O'brien7, Alessandra Tedeschi8, Constantine Tam9
1Fred Hutchinson Cancer Center and University of Washington, Seattle, Washington, United States ofAmerica, 2Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber Cancer
Institute and Harvard Medical School, Boston, MA, United States of America, 3BeiGene Netherlands B.V.,
Schiphol, The Netherlands, 4BeiGene USA, Inc., San Mateo, CA, United States of America, 5Evidera,Montreal, Canada, 6Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center,New York, United States of America, 7University of California, Irvine, CA, United States of America, 8ASSTGrande Ospedale Metropolitano Niguarda, Milan, Italy, 9Alfred Hospital and Monash University,Melbourne, Victoria, Australia
Background: Next-generation Bruton’s tyrosine kinase inhibitors (BTKis) have led to changes in thetreatment algorithm for patients with high-risk relapsed/refractory (R/R) CLL; defined based on thepresence of genetic mutations and a high unmet need.
Aims: Given the lack of head-to-head trials comparing these treatments in R/R CLL, a Network Meta
Analysis (NMA) was performed to estimate the relative efficacy of BTKis used to treat high-risk patients.
Methods: Randomized controlled trials ALPINE (zanubrutinib vs. ibrutinib), ELEVATE-RR (acalabrutinibvs. ibrutinib), and ASCEND (acalabrutinib vs. bendamustine + rituximab/idelalisib + rituximab [BR/IR])
were included in the NMA. High-risk populations were defined based on the pre-specified subgroups
within each trial, including patients with del17p and/or TP53 mutations in ALPINE (zanubrutinib: 75/327
and ibrutinib: 75/325), ASCEND (acalabrutinib: 44/155 and BR/IR: 42/155), and del17p/del11q in
ELEVATE-RR (acalabrutinib: 268/268 and ibrutinib: 265/265). Bayesian NMAs were used to estimate
hazard ratios (HRs) or odds ratios (ORs) with 95% credible intervals (CrIs), and probability better (PB) for
zanubrutinib versus all other treatments. Outcomes analysed included investigator-assessed
progression-free survival (PFS), overall survival (OS), overall response (ORR), and complete response(CR). Given the timing of the included trials in relation to the COVID-19 pandemic, ALPINE data wereanalyzed with and without adjustment for COVID-19 related deaths.
Results: The NMA found a statistically significant improvement in PFS for zanubrutinib overacalabrutinib in high-risk patients and a trend towards improvement in OS, ORR, and CR (Table).
Zanubrutinib led to statistically significant improvements in PFS versus ibrutinib (HR [95% CrI]: 0.49
[0.30, 0.78], PB: 99.9%) and BR/IR (0.12 [0.05, 0.26], PB: 100.0%). For OS, zanubrutinib showed a trend
towards improvement versus ibrutinib (0.59 [0.31, 1.12] PB: 94.8%) and BR/IR (0.64 [0.24, 1.74] PB:80.7%).
Summary/Conclusion: This NMA found zanubrutinib to be the most efficacious BTKi for patients withhigh-risk R/R CLL, offering significantly delayed disease progression, and favorable survival and response
versus alternative BTKi treatments.

EHA 2024

EHA 2024