Abstract 1257: Early blood uMRD correlates with improved PFS in patients with CLL
Authors: Abdelgawad Ibrahim Y. , Suleiman Ahmed A. , Chyla Brenda , Ghanim Majd , Salem Ahmed H. , Badawi Mohamed 
Published: June 2022

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: &lt; 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 (&gt; 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&lt;0.001). Pts with residual disease &lt; 10-3 (&lt;1 CLL cell/1,000 leukocytes) at ~6 M were more likely to demonstrate PB uMRD at 12 M (72% vs 6%, p&lt;0.001) compared to pts with residual disease ≥10-3 at this assessment. Neither ALC or percent change in lymphocytes at 1, 3, 6, and 9 M of treatment correlated with PB uMRD.

In this R/R CLL population who received continuous dosing of venetoclax, uMRD at ~6 M correlated with PFS outcomes. Additionally, MRD levels at ~6 M of therapy correlated with uMRD at 12 M. These suggest that including PB MRD assessments at early timepoints may be a useful tool in assessing efficacy and informing RP2D decisions during the development of novel agents in this indication.

Citation Format: Ibrahim Y. Abdelgawad, Ahmed A. Suleiman, Brenda Chyla, Majd Ghanim, Ahmed H. Salem, Mohamed Badawi. Early blood uMRD correlates with improved PFS in patients with CLL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1257.