Network meta-analysis of novel targeted therapies for relapsed/refractory chronic lymphocytic leukemia

Abstract

Background: The recent development of new antileukemic therapies (anti-CD20 monoclonal antibodies, Bruton tyrosine kinase inhbitors, phosphoinositide 3-kinase inhibitors, and B-cell lymyphoma-2 antagonists) improved the progression-free survival (PFS) compared with selected standard regimens in clinical trials for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Unfortunately, the relative efficacy of all possible therapeutic options remains unknown because there is no direct evidence for all possible comparisons. Objectives: We aimed to compare the efficacy and safety of novel agents, chemotherapy, and immunotherapy using a Bayesian network meta-analysis (NMA). Design: Systematic literature review with Bayesian NMA. Methods: An extensive systematic literature review of randomized clinical trials for relapsed/refractory CLL was performed. We searched for articles indexed in medical databases (MEDLINE, Embase, The Cochrane Library) and gray literature that could be further implemented into the Bayesian NMA. Results: The systematic search identified 15 randomized trials that formed networks comparing PFS, overall survival (OS), overall response rates, and serious adverse events. Our study showed that all regimens containing novel agents significantly prolonged PFS compared with standard chemoimmunotherapy and immunotherapy. Among targeted drugs, venetoclax (VEN) + rituximab (RTX) had comparable efficacy in terms of PFS to zanubrutinib (ZAN) [hazard ratio (95% credible interval), 1.10 (0.59–2.08)], acalabrutinib (ACA) [0.78 (0.47–1.30)], ibrutinib (IBR) monotherapy [0.72 (0.41–1.27)], and other IBR-based regimens. ZAN was superior to IBR monotherapy [0.65 (0.49–0.86)] but not to ACA [0.71 (0.49–1.02)]. There were no significant differences in OS in any of the above comparisons. Conclusion: All novel therapies have better efficacy than chemoimmunotherapy and immunotherapy regimens. Among novel agents, the relative efficacy of VEN + RTX was similar to all BTKi, while ZAN was superior to IBR and comparable to ACA. Trial registration: PROSPERO CRD42022304330.