Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: A systematic review and meta-analysis.

Abstract

e19003 Background: Chronic lymphocytic leukemia (CLL) patients with undetectable minimal residual disease (U-MRD) (i.e., < 10-4) after upfront chemotherapy (CT) or chemo-immunotherapy (CIT) have better outcomes than those with detectable MRD (D-MRD). To validate the importance of achieving U-MRD and to assess the magnitude of improvement in progression free survival (PFS) and overall survival (OS) we conducted a systematic review and meta-analysis. Methods: The screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The search strategy yielded 365 records, including 22 articles assessed for eligibility. Results: Eleven studies comprising 2457 CLL patients treated upfront with CT or CIT were considered suitable for inclusion in the quantitative meta-analysis. Four studies (n = 924) analyzed the impact of U-MRD on both PFS and OS while 8 studies (n = 1984) provided data only on PFS and 6 (n = 1074) exclusively on OS. U-MRD status was associated with significantly longer PFS overall (P < .001) and in patients who achieved complete remission (CR) according to the International Workshop on CLL (IWCLL) guidelines (P = 0.01). Tests of heterogeneity revealed significant differences across studies evaluating PFS in both patients with U-MRD (Q = 49.27; P = 0.00; I2= 80%) and D-MRD (Q = 199.15; P = 0.00; I2= 95%). OS was also longer in patients with U-MRD overall (P < .001). Test of heterogeneity revealed no significant differences across studies evaluating OS in patients with U-MRD (Q = 9.16; P = 0.06; I2= 56%). Of note, U-MRD did not predict for a longer OS in patients who achieved IWCLL CR. (P = 0.82). This contrasts with data from single series and needs prospective assessment. Conclusions: This study validates the importance of achieving U-MRD in newly diagnosed patients with CLL treated with CT or CIT and provides quantitative evidence of the improvement regarding PFS and OS. MRD status should be incorporated as endpoint into prospective clinical trials and in the evaluation of new agents for CLL therapy as already accepted by the European Medicines Agency (EMA). The clinical significance of MRD in patients treated with BCR or BCL2 inhibitors is largely unknown and warrants study.