Abstract 1257: Early blood uMRD correlates with improved PFS in patients with CLL

The approval of targeted therapies has greatly improved outcomes for patients (pts) with chronic lymphocytic leukemia (CLL) in both 1L and relapsed/refractory (R/R) settings. The use of long-term outcomes such as progression free survival (PFS) and overall survival (OS) to inform early drug development can extend timelines and delay approval of potentially beneficial novel treatments. Establishing correlations between short-term treatment effects and long-term outcomes could shorten development timelines. Minimal residual disease (MRD) is a sensitive indicator of disease burden, with achievement of undetectable MRD (uMRD: < 1 CLL in 10,000 leukocytes [10-4]) either during or at the end of therapy being prognostic of prolonged PFS and OS. Our current work explores correlations between PFS and earlier dynamic changes in lymphocyte counts and peripheral blood (PB) MRD as potential tools for guiding drug development decisions in CLL. Data from five trials (NCT numbers 01328626, 01889186, 02141282, 02756611 (receiving Venetoclax monotherapy and primarily R/R CLL pts) and 01682616 (R/R CLL pts receiving venetoclax + rituximab therapy) were analyzed. PB MRD was quantified by either flow cytometry or next generation sequencing at various timepoints. Many of these pts had high risk features such as 17pDEL or prior BCRi therapy. The relationships between absolute lymphocyte count (ALC) and percent change in lymphocytes at 1, 3, 6, and 9 months (M) of treatment and PB MRD status were explored. Additionally, the relationship between PB MRD levels at 6±2 M and achievement of uMRD was assessed. Lastly, we evaluated the relationship between PB MRD status at different time points (6±2, 9 and 12 M) and PFS using Kaplan Meier plots. Across the trials, 708 CLL pts were treated, with 496 pts having PB MRD assessments at any time on therapy. PB uMRD rate of the evaluable population was 47.6% (236/496). Analysis of pts with PB MRD assessments at ~6 M (6±2 M, n=310) demonstrated that achievement of uMRD correlated with improved PFS (with median PFS of 56 M compared to 26 M in pts who had detectable MRD, p=0.037). Moreover, pts with residual disease in the PB (> 10-4) at ~6 M and achieved uMRD later while on therapy had a significantly lower residual disease at this timepoint than pts who did not achieve uMRD (p