Efficacy and safety of obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia: A reappraisal for low-resource settings

Abstract

Abstract Background: While chlorambucil has largely been replaced by novel targeted therapies in the treatment of chronic lymphocytic leukemia (CLL) in high-income countries, it remains one of the few accessible treatment options in many low- and middle-income regions. When combined with the anti-CD20 monoclonal antibody obinutuzumab, chlorambucil has shown improved outcomes, particularly in elderly patients or those with comorbidities. This study aims to reassess the efficacy and safety of this regimen in light of global disparities in access to newer therapies. Aims: To evaluate the efficacy and safety of obinutuzumab plus chlorambucil in treatment-naive CLL, with particular relevance to settings where access to first-line targeted therapies remains limited. Methods: A systematic review of PubMed, Embase, and Cochrane Central databases was conducted in June 2025 to identify randomized controlled trials (RCTs) assessing the obinutuzumab-chlorambucil combination in previously untreated CLL patients. Primary endpoints included overall response rate (ORR), complete response rate (CRR), incidence of cardiovascular events, neutropenia, all-cause mortality, and CKD-related mortality. Meta-analysis was performed using a random-effects model in R (v4.4.2) to calculate 95% confidence intervals (CI). Results: A total of 956 articles were screened, of which 5 RCTs comprising 1,347 patients were included; 947 (43.28%) received obinutuzumab plus chlorambucil. The pooled ORR was 78.56% (95% CI: 74.94–81.97) (Figure 1A), and CRR was 13.4% (95% CI: 4.34–26.25) (Figure 1B). Cardiovascular events occurred in 3.37% (95% CI: 1.09–6.69) (Figure 2A), while neutropenia was the most common hematologic toxicity with 14.90% (95% CI: 12.28–17.52) (Figure 2B). All-cause mortality was 7.87% (95% CI: 4.61–12.78) (Figure 2C), with CKD-related mortality at 1.18% (95% CI: 0.26–4.84) (Figure 2D) Conclusion: Despite being phased out in wealthier health systems, chlorambucil remains a relevant therapeutic option when combined with obinutuzumab—especially in regions where modern targeted therapies are unavailable. This regimen offers a viable, evidence-backed alternative for treatment-naive CLL patients in low-resource settings, with acceptable safety and efficacy profiles.