Minimal residual disease as a prognostic marker in chronic lymphocytic leukemia: A meta-analysis across chemoimmunotherapy and targeted therapies

Abstract Background Minimal Residual Disease (MRD) assessment is increasingly utilized in the management of Chronic Lymphocytic Leukemia (CLL). Prior studies have demonstrated that MRD negativity at the end of treatment is associated with improved survival outcomes. However, the majority of these studies focused on chemoimmunotherapy regimens. Data on the prognostic significance of MRD status in patients treated with targeted agents such as BCL-2 inhibitors or Bruton Tyrosine Kinase (BTK) inhibitors remain limited. Therefore, we conducted an updated systematic review and meta-analysis to evaluate the impact of end-of-treatment MRD status on progression-free survival (PFS). Methods We conducted a systematic search of PubMed and Cochrane databases. Two reviewers independently screened studies for inclusion. Eligible studies were randomized clinical trials of first-line CLL therapies, published in English, that evaluated the effect of MRD status on PFS, using an MRD threshold of ≤0.01%. Data including MRD status and 3-year PFS were extracted in a standardized manner. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model (Mantel-Haenszel method). Meta-analysis was performed using Review Manager (RevMan) Version 5.4 (The Cochrane Collaboration, 2020). Results A total of 13 studies comprising 3,101 patients were included. Of these, 14 study arms investigated chemoimmunotherapy, 5 venetoclax-containing regimens, and 3 ibrutinib-containing regimens. MRD assessment was performed using multicolor flow cytometry (n=10), next-generation sequencing (n=2), or both (n=1). MRD was assessed in peripheral blood (n=8), bone marrow (n=3), or either (n=2). Even though some studies have multiple MRD assessment points, end-of-treatment MRD, mostly within 2-3 months after completion of the treatment, was used to correlate with PFS. In patients treated with chemoimmunotherapy, MRD negativity was associated with significantly higher PFS (OR 10.21; 95% CI: 7.90–13.21; p < 0.00001; I² = 0%). In venetoclax-treated patients, MRD negativity was also significantly associated with improved PFS (OR 3.47; 95% CI: 1.69–7.11; p = 0.006; I² = 73%). However, in patients treated with ibrutinib-containing regimens, MRD negativity was not significantly associated with higher PFS (OR 1.87; 95% CI: 0.85–4.12; p = 0.25; I² = 25%). Conclusion This meta-analysis reinforces the prognostic value of MRD negativity in patients receiving chemoimmunotherapy or venetoclax-based regimens for CLL. However, in patients treated with ibrutinib, MRD status was not significantly associated with PFS. These findings suggest that MRD may not be a reliable surrogate endpoint in the context of BTK inhibitor therapy or that such agents may achieve durable disease control even in MRD-positive patients. These findings highlight the need for further research to better define the role of MRD as a prognostic marker or as a guide for treatment decisions in patients receiving BTK inhibitors.