Efficacy and Safety of First-line Targeted Therapies in Physically Fit Patients With Chronic Lymphocytic Leukemia: A Systematic Review and Network Meta-analysis

Clin Ther. 2025 May;47(5):e12-e20. doi: 10.1016/j.clinthera.2025.01.009. Epub 2025 Feb 13.

Abstract

Purpose: Targeted therapies are promising treatment options for fit patients with untreated chronic lymphocytic leukemia (CLL). However, there is a lack of data on their relative efficacy and safety. The aim of this systematic review was to assess the relative efficacy and safety of first-line targeted therapies (including venetoclax [VEN], obinutuzumab [OBI], ibrutinib [IBR], and other options) for physically fit patients with untreated CLL.

Methods: A systematic literature review of major medical databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) and additional data sources was conducted to identify randomized controlled trials providing data of interest. Progression-free survival (PFS) and undetectable minimal residual disease (MRD(-)) in peripheral blood (PB) were analyzed, along with other end points. A Bayesian network meta-analysis was used for data analysis. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, and its protocol was registered in the International Prospective Register of Systematic Reviews (CRD42023393903).

Findings: The network meta-analysis results reported no significant differences between targeted therapies for PFS. However, IBR + VEN and VEN + OBI + IBR reported the highest probability of being the most effective options based on surface under the cumulative ranking curve values. For MRD(-)PB, VEN + OBI + IBR reported a significant advantage over other therapies, with surface under the cumulative ranking curve values confirming it as the most effective option in this term.

Implications: Targeted therapies may offer a promising treatment option for fit patients with previously untreated CLL. Among the therapies assessed, IBR + rituximab and VEN + OBI + IBR emerge as the most effective therapeutic options for prolonging PFS, while VEN + OBI + IBR and VEN + OBI reported favorable outcomes in achieving MRD(-)PB. However, further research is needed to validate these findings.

Keywords: Ibrutinib; Minimal residual disease; Obinutuzumab; Progression-free survival; Venetoclax.

Publication types

  • Systematic Review
  • Network Meta-Analysis

MeSH terms

  • Adenine / analogs & derivatives
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents* / adverse effects
  • Antineoplastic Agents* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Bayes Theorem
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell* / mortality
  • Molecular Targeted Therapy* / methods
  • Neoplasm, Residual
  • Piperidines
  • Progression-Free Survival
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use
  • Randomized Controlled Trials as Topic
  • Sulfonamides / adverse effects
  • Sulfonamides / therapeutic use
  • Treatment Outcome

Substances

  • Piperidines
  • Adenine
  • ibrutinib
  • obinutuzumab
  • venetoclax
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Sulfonamides
  • Pyrimidines
  • Bridged Bicyclo Compounds, Heterocyclic