Minimal Residual Disease Status Displays Association with PFS in CLL

Fausto Alfredo Rios-Olais, MD

Assessing minimal residual disease (MRD) status as a clinical trial end point and as a surrogate of progression-free survival (PFS) may improve trial efficiency, according to findings from a systemic review and meta-analysis published in JAMA Oncology that showed MRD status was associated with PFS in patients with chronic lymphocytic leukemia (CLL).

Data from the analysis demonstrated that undetectable MRD at 0.01% was associated with a HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. The median PFS was not yet reached among patients with undetectable MRD (n = 1265) or detectable MRD (n = 1075), however the estimated 24-month PFS rates were 91.9% (95% CI, 88.8%-95.2%) vs 75.3% (95% CI, 64.7%-87.6%), respectively (P < .001). Moreover, undetectable MRD was also associated with PFS among patients treated in the frontline setting (HR, 0.24; 95% CI, 0.18-0.33), those with relapsed or refractory disease (HR, 0.34; 95% CI, 0.16-0.71), and in studies that used time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40).

“In this systematic review and meta-analysis of 11 prospective clinical trials including 2765 patients with CLL treated with targeted agents or obinutuzumab [Gazyva]-based therapy, MRD status was associated with PFS in the first-line treatment setting and with time-limited therapy. Fausto Alfredo Rios-Olais, MD, hematology fellow at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City, Mexico, and coauthors wrote in the publication. “These findings may have implications for clinical trial design and provide a rationale for using MRD as an end point for accelerated drug registration.”

To conduct their analysis, investigators identified clinical studies in CLL using searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023. Study authors selected prospective, single-arm, and randomized clinical trials which examined targeted agents or obinutuzumab-based treatment and reported PFS by MRD status. Investigators excluded abstracts, retrospective studies, review articles, case reports, case series, maintenance treatment studies, duplicate studies, non-English language publications, and studies lacking comprehensive details on MRD and/or survival outcomes by MRD status from their analysis.

The survival probabilities and HR analyses were conducted for PFS by MRD status. Investigators used a random-effects model to perform meta-analyses. The analysis included data from the randomized, phase 3 MURANO (NCT02005471), E1912 (NCT02048813), HELIOS (NCT01611090), CLL-11 (NCT01010061), GENUINE (NCT02301156), GLOW (NCT03462719), CLL-14 (NCT02242942), CLL-13 (NCT02950051), and iLLUMINATE (NCT02264574) trials, as well as from the phase 2 non-randomized GREEN (NCT01905943) and M13-982 (NCT01889186) studies.

Additional findings from the analysis revealed that patients treated in the frontline setting achieved estimated 24-month PFS rates of 93.5% (95% CI, 90.9%-96.2%) in the undetectable MRD group (n = 1088) compared with 77.7% (95% CI, 64.9-93.0) in the detectable MRD group (n = 847; P < .001). Patients with relapsed/refractory disease experienced estimated 24-month PFS rates of 83.5% (95% CI, 70.8%-98.4%) vs 68.8% (95% CI, 50.2%-94.4%) in the undetectable MRD (n = 177) and detectable MRD (n = 228) arms, respectively. Patients who received time-limited therapy experienced estimated 24-month PFS rates of 90.7% (95% CI, 86.3%-95.3%) vs 55.5% (95% CI, 46.8%-65.9%) in the undetectable MRD (n = 1119) and detectable MRD (n = 640) arms, respectively (P < .001).

Data from 2 trials that reported MRD-associated PFS according to standard response criteria demonstrated that patients with a complete response (CR) and undetectable MRD (n = 427) achieved the longest PFS. PFS was found to be similar among patients with undetectable MRD and a partial response (PR; n = 292) and those with a CR and detectable MRD (n = 95); PFS was the shortest in patients with a PR and detectable MRD (n = 215).

“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,” Rios-Olais and coauthors wrote in conclusion.

Reference

1. Rios-Olais FA, McGary AK, Tsang M, et al. Measurable residual disease and clinical outcomes in chronic lymphocytic leukemia: A systematic review and meta-analysis. JAMA Oncol. Published online July 11, 2024. doi:10.1001/jamaoncol.2024.2122