Relative Efficacy of Systemic Treatments for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: A Network Meta-Analysis According to 17p Deletion/TP53 Mutations

Introduction: The treatment landscape forrelapsed/refractory chronic lymphocytic leukemia (R/R CLL) has significantly advanced with the introduction of novel targeted therapies. Although these treatments have shown improved outcomes for R/R CLL patients, no single standard of care has been established. This network meta-analysis aims to evaluate the relative efficacy of systemic treatments for R/R CLL, focusing on key genetic mutations, specifically 17p deletion and TP53 mutations.

Methods: We conducted a systematic literature review to identify all publicly available randomized controlled trials (RCTs) using PubMed, EMBASE, the Cochrane database, and several meeting abstracts through February 2024. A Bayesian network meta-analysis with fixed-effects models was employed to estimate hazard ratios (HRs) for progression-free survival (PFS) with 95% credible intervals (CIs) across all treatment options and to determine the ranking of the included regimens. Ibrutinib was used as reference treatment.

Results: Twelve trials involving 4,437 patients and 13 treatment options were included in the meta-analysis: three Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, and zanubrutinib), two BTK inhibitors combined with other treatments (ibrutinib plus rituximab plus bendamustine [RB] and ibrutinib plus rituximab), two phosphoinositide 3-kinase (PI3K) inhibitors (idelalisib and duvelisib), three PI3K inhibitors combined with other treatments (idelalisib plus ofatumumab, idelalisib plus RB, idelalisib plus rituximab), three anti-CD20-based treatment (RB, ofatumumab, and rituximab), and one BCL-2 inhibitor (venetoclax plus rituximab). Venetoclax plus rituximab and zanubrutinib emerged as the most effective treatments for the overall R/R CLL population, showing the lowest hazard ratios (HR 0.62, 95% CI 0.32-1.20 and HR 0.65, 95% CI 0.49-0.86, respectively) versus ibrutinib, and were ranked as the best agents (surface under the cumulative ranking curve [SUCRA] value of 90% for both) among the included drugs. In the 17p deletion/TP53 mutation subgroup, zanubrutinib demonstrated the most favorable efficacy (HR 0.52, 95% CI 0.31-0.88 versus ibrutinib) with the highest SUCRA value (97%). For patients without these mutations, venetoclax plus rituximab was the most effective (HR 0.49, 95% CI 0.26-0.94 versus ibrutinib) with a SUCRA value of 94%.

Conclusions: Our findings highlight the superior efficacy of venetoclax plus rituximab and zanubrutinib for treating R/R CLL and confirm that the role of each regimen may vary depending on clinically significant mutations.

No relevant conflicts of interest to declare.