ÌÇÐÄvlog

QuestionÌý What is the association between measurable residual disease (MRD) and progression-free survival in chronic lymphocytic leukemia?

FindingsÌý In this systematic review and meta-analysis of 11 prospective clinical trials including 2765 patients with chronic lymphocytic leukemia treated with targeted agents or obinutuzumab-based therapy, MRD status was associated with progression-free survival in the first-line treatment setting and with time-limited therapy.

MeaningÌý These findings may have implications for clinical trial design and provide a rationale for using MRD as an end point for accelerated drug registration.

ImportanceÌý Measurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development.

ObjectiveÌý To assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment.

Data SourcesÌý Clinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023.

Study SelectionÌý Prospective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded.

Data Extraction and SynthesisÌý Study sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted.

Main Outcomes and MeasuresÌý Analyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model.

ResultsÌý A total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40).

Conclusions and RelevanceÌý The findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.