Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx)

Introduction: The randomized Phase III MURANO study (NCT02005471) compared fixed-duration VenR with standard bendamustine-rituximab (BR) in R/R CLL. Deep responses with uMRD were associated with superior progression-free survival (PFS) of VenR vs BR with 48 months (mo) follow-up (f/u). We now report long-term MRD kinetics and updated efficacy outcomes, including re-exposure to VenR (to be presented), with a 5 year (yr) median follow-up (clinical cutoff date May 8, 2020).

Methods: As published, pts were randomized to VenR (Ven 400 mg daily for 2 yrs + standard dose R for the first 6 mo) or B (70 mg/m²)R (6 mo). A sub-study was introduced in 2018, allowing pts who developed progressive disease (PD) following Tx with BR or VenR to receive the MURANO VenR regimen. PFS was based on investigator assessment. Peripheral blood MRD was analyzed centrally by allele-specific oligonucleotide polymerase chain reaction and/or flow cytometry. Pts were categorized by MRD status as previously reported, using <10^-4 threshold for uMRD. MRD conversion was defined as 2 consecutive assays detecting MRD or PD in pts who previously had uMRD. Genomic complexity (GC) and del(17p) status were assessed by array comparative genomic hybridization. GC was defined as ≥3 copy number variations (CNV). All p-values are descriptive.

Results: 389 pts were enrolled (VenR, n=194; BR, n=195). With a median f/u of 59.2 (range, 0–71.5) mo, the PFS benefit with VenR over BR was sustained (HR, 0.19 [95% CI: 0.15–0.26]; p<0.0001). Median PFS was 53.6 (95% CI: 48.4–57.0) mo for VenR and 17.0 (95% CI: 15.5–21.7) mo for BR. For pts who completed the full 2 yrs of Ven Tx (n=130), PFS estimates 36 mo post-end of treatment (EOT) were ~51.1% (95% CI: 40.2–61.9). Overall survival (OS) benefit was maintained for pts treated with VenR vs BR (HR, 0.40 [95% CI: 0.26–0.62]; p<0.0001), with 5-yr OS estimates of 82.1% (95% CI: 76.4–87.8) for VenR and 62.2% (95% CI: 54.8–69.6) for BR.

Improved OS outcome was observed among the VenR pts that reached EOT without PD and had uMRD (83/118) compared with those with MRD (35/118), with 3-yr post-EOT survival estimates of 95.3% (95% CI: 90.0–100.0) vs 85.0% (95% CI: 72.8–97.2), respectively (Figure 1). Of the pts with uMRD at EOT, 32/83 had not shown PD and remained uMRD at the 5-yr update, 4/83 had PD without prior confirmed MRD conversion and 47/83 had MRD conversion. Median time to MRD conversion from EOT was 19.4 (95% CI: 8.7–28.3) mo. Of the 47/83 pts with confirmed MRD conversion, 19 subsequently developed PD by International Workshop on CLL criteria with a median time to PD from MRD conversion of 25.2 (95% CI: 19.4–30.4) mo. These 19 pts exhibited more rapidly increasing rates of MRD post-EOT than pts that had MRD conversion but were PD-free (Figure 2).

Among pts that were uMRD at EOT, the baseline presence of del(17p), GC and unmutated immunoglobulin heavy chain gene (IGVH) were each associated with increased risk of MRD conversion and subsequent PD post-EOT (Table 1). All 4 pts with del(17p) experienced MRD conversion with subsequent PD. 8/18 (44%) pts with GC vs 8/40 (20%) pts without GC eventually converted to MRD and developed PD. The rate of MRD conversion with eventual PD was also higher among those with unmutated IGVH (21/56; 37%) than those without (1/23; 4%). Once uMRD at EOT was achieved, pts without del(17p) or GC, or with mutated IGVH, were more likely to maintain uMRD or experience MRD conversion without subsequent PD at this follow-up (Table 1).

No new safety signals were identified. Excluding non-melanoma skin cancers, 2 second primary malignancies (VenR [acute myeloid leukemia and multiple myeloma]) were reported since the previous update. Rates of Richter transformation remained balanced between treatment arms (7 on VenR, 6 on BR).

Following PD on the main study, 29 pts were enrolled in the sub-study (re-treatment; n=21, crossover; n=8). Further data on their biologic profile, updated response rates, and MRD in the re-treatment cohort will be presented.

Conclusions: Five-yr data from MURANO demonstrate sustained PFS and OS benefit with VenR vs BR. In the VenR cohort, uMRD at EOT is associated with improved OS. Unmutated IGVH, del(17p) and GC (≥3 CNV) are associated with higher rates of MRD conversion and subsequent PD after attaining uMRD at EOT. Overall, a substantial proportion of pts who completed Ven Tx retained uMRD 36 mo after treatment cessation, displaying durable response following 2-yr fixed-duration VenR.