Venetoclax Plus Rituximab Continues to Demonstrate Survival and MRD Benefits in CLL

John Seymour, MBBS, FRACP, PhD

Fixed-duration venetoclax (Venclexta) plus rituximab (Rituxan; VenR) has shown sustained progression-free survival (PFS), overall survival (OS), and minimal residual disease (MRD) benefits vs bendamustine plus rituximab (BR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), regardless of high-risk biomarkers, according to findings from a 5-year update of the phase 3 MURANO trial (NCT02005471).¹

The results, which were published in Blood, showed that at 5 years from the start of treatment (3 years post-treatment cessation), the median PFS in the VenR arm was 53.6 months (95% CI, 48.4-57.0) vs 17.0 months (95% CI, 15.5-21.7) in the BR arm (HR, 0.19; 95% CI, 0.15-0.26; P < .0001). Additionally, the 5-year OS rate was 82.1% (95% CI, 76.4%-87.8%) in the VenR arm vs 62.2% (95% CI, 54.8%-69.6%) in the BR arm (HR, 0.40; 95% CI, 0.26-0.62; P < .0001).

Regarding MRD, 42.8% of patients who had completed the 2-year VenR regimen and who had undetectable MRD (uMRD) at the end of treatment (n = 83) displayed a superior 3-year post-treatment cessation OS estimate of 95.3% (95% CI, 90.0%-100.0%) vs 72.9% (95% CI, 46.4%-99.5%) of those from this arm who had high MRD-positive disease (n = 12; P = .039); this rate was 91.3% (95% CI, 79.8%-100.0%) in those with low MRD-positive disease.

Moreover, a population-based logistic growth model showed a slower median MRD doubling time after the end of treatment with VenR (93 days) vs BR (53 days; P = 1.2 x 10–7).

“In the current analysis, MRD level continued to be a robust predictor of PFS. uMRD status at the end of treatment was also predictive of improved OS. These data are congruent with previous analyses,” lead study author John Seymour, MBBS, FRACP, PhD, of the Peter MacCallum Cancer Centre, and colleagues, wrote in the paper.

MRD in CLL can quantify the depth of time-limited treatment response, with MRD at the end of treatment being a predictor of long-term clinical treatment outcomes. Achievement of uMRD is also associated with improved PFS and OS.

The MURANO trial sought to determine the safety and efficacy of fixed-duration VenR vs BR in patients with relapsed/refractory CLL. A total of 389 patients were randomized to either 2 years of VenR (n = 194) or 6 months of BR (n = 195). Primary analysis of this trial reported a longer PFS in the VenR arm, with this benefit observed in all subgroups analyzed.

A total of 130 patients from the MURANO trial completed 2 years of treatment with VenR without PD. The median duration of follow-up from trial enrollment to the beginning of the updated analysis was 59.2 months (range, 0-71.5).

The primary end point of the 5-year follow-up was PFS, which was defined as the time from randomization to first occurrence of PD or death. Patients were categorized by peripheral blood MRD status, which served as a secondary end point. Other secondary end points included OS, time to next treatment (TTNT), complete response rates, partial response rates, and safety assessments.

Additional data from this analysis showed that VenR improved TTNT vs BR (HR, 0.26; 95% CI, 0.20-0.35; P < .0001). The median TTNT was 57.8 months (95% CI, 55.1–not estimable [NE]) in the VenR arm vs 23.9 months (95% CI, 20.7-29.5) in the BR arm.

The presence of high-risk cytogenetic and/or molecular abnormalities was associated with a shorter median PFS in patients in the VenR arm. Specifically, those with unmutated IGHV experienced a median PFS of 52.2 months, and the median PFS was NE in patients with mutated IGHV (HR, 2.96; 95% CI, 1.64-5.34; P = .0002). Patients with 17p deletion and/or a TP53 gene mutation had a median PFS of 37.4 months vs 56.6 months in those with TP53 wild-type disease (HR, 2.04; 95% CI, 1.32-3.15; P = .010). Additionally, patients with genomic complexity had a median PFS of 41.7 months vs 59.8 months in those with no genomic complexity (HR, 2.50; 95% CI, 4.00-1.56; P < .0001). Similar patterns were observed in patients from the BR arm, although with lower median PFS than shown in the VenR arm.

Additional data regarding OS indicated that although the OS benefit for patients treated with VenR was maintained, the median OS had not yet been reached for either arm.

OS assessment by IGHV mutation status, 17p deletion status, TP53 mutation status, and genomic complexity favored VenR vs BR. Among patients in the VenR arm, those with IGHV mutations had the highest 5-year OS estimate of 92.3%, and those with 17p deletion or TP53 mutations had the lowest estimate of 70.9%.

In terms of MRD conversion, at the 5-year update, 4.8% (n = 4) of patients from the VenR arm who had completed the 2-year treatment and had uMRD at the end of treatment had PD without prior MRD conversion. A total of 56.6% (n = 47) of these 83 patients had confirmed MRD conversion, and 40.4% (n = 19) of this subset subsequently developed PD, with a median time from MRD conversion to PD of 25.2 months (95% CI, 19.4-30.4). Additionally, 38.6% (n = 32) of patients who received VenR continued to have uMRD without PD. Overall, the median time from the end of treatment to MRD conversion was 19.4 months (95% CI, 8.7-28.3).

Among patients who had uMRD at the end of treatment, those who had baseline unmutated IGHV, 17p deletion, or genomic complexity had an increased likelihood of developing PD. Specifically, the rate of MRD conversion with eventual PD was 37.5% (n = 21) in the 56 patients with unmutated IGHV vs 4.3% (n = 1) in the 23 patients with mutated IGHV. A total of 44.4% (n = 8) of the 18 patients with genomic complexity who had uMRD at the end of treatment experienced MRD conversion and developed PD. Additionally, all 4 patients with 17p deletions who had uMRD at the end of treatment experienced MRD conversion with subsequent PD.

Of the 23 patients who had low MRD-positive disease at the end of treatment, 47.8% (n = 11) displayed rising MRD prior to the end of treatment; the rest showed stable MRD levels.

Among the 284 patients who completed treatment without prior PD, 211 were eligible for inclusion in the population-based MRD analysis; this included 91 patients in the VenR arm and 120 patients in the BR arm. The median duration of MRD data collection following the end of treatment was 735 days for the VenR arm vs 395 days for the BR arm.

This follow-up analysis confirmed the statistical significance of the effect of treatment on MRD level at the end of treatment and MRD growth rate, with the MRD level at the end of treatment in the VenR arm being 0.094-fold that in the BR arm (95% CI, 0.034-0.266) and the MRD growth rate in the VenR arm being 0.51-fold that in the BR arm (95% CI, 0.41-0.64).

For all patients, the median treatment-free interval was 23.7 months (range, 3.3-43.8), with 77.0% (n = 67) of patients in the VenR arm who experienced PD and 83.1% (n = 123) of those in the BR arm who experienced PD receiving a subsequent therapy. Of these patients from the VenR arm, 47.8% (n = 32) received a venetoclax-based therapy, 26.9% (n = 18) received a BTK inhibitor, 22.4% (n = 15) received chemoimmunotherapy, and 3.0% (n = 2) received another novel agent. Similarly, of the patients from the BR arm who received a subsequent therapy, 12.2% (n = 15) received a venetoclax-based therapy, 58.5% (n = 72) received a BTK inhibitor, 19.5% (n = 24) received chemoimmunotherapy, and 9.8% (n = 12) received another novel agent.

Of patients from the VenR arm who received a subsequent therapy, the best objective response rate (ORR) to subsequent venetoclax-based therapy was 72.2%, and the best ORR to subsequent BTK inhibitors was 100.0%.

This updated analysis revealed no new safety signals. Safety data included only post-treatment adverse effects. Notably, in the VenR arm, 2 additional secondary primary malignancies, acute myeloid leukemia and plasma cell myeloma, have been reported since the previous update of this trial. Additionally, Richter’s transformation rates remained balanced between the arms, with 7 cases appearing in the VenR arm and 6 cases appearing in the BR arm.

“This 5-year update of MURANO demonstrates that survival benefits of VenR treatment over BR are maintained 3 years post-treatment cessation in patients with [relapsed/refractory] CLL,” the study authors wrote.

Longer follow-up of the MURANO trial is necessary to determine the clinical relevance of markers such as MRD status, uMRD durability, and characteristics of patients with early relapse. Going forward, further studies investigating the role of uMRD achievement in disease control are needed to determine whether MRD-based treatments can lead to sustained MRD remission. Additionally, the optimization of intermittent venetoclax-based therapy in patients with high-risk biomarkers requires further investigation.

Reference

Seymour JF, Kipps TJ, Eichhorst B, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. Published online May 23, 2022. doi:10.1182/blood.2021015014