Venetoclax Plus Rituximab Provides Long-Term Survival Benefit in Relapsed/Refractory CLL

Treatment with fixed-duration venetoclax (Venclexta) plus rituximab (Rituxan; VenR) continued to show superior survival benefit compared with bendamustine and rituximab (BR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to 7-year follow up data from the phase III MURANO trial (NCT02005471) presented at the 2023 EHA Congress.

The final 7-year follow-up and retreatment substudy of the phase III MURANO trial, presented by co-author Dr. Arnon Kater of Amsterdam University Medical Centers, found that as of the final data cutoff in August 2022, the 194 VenR-treated patients had a median progression-free survival (mPFS) of 54.7 months (95% CI, 52.3-59.9) vs 17.0 months (95% CI, 15.5-21.7) for the 195 BR-treated patients (HR = 0.23).

During the MURANO trial, 389 patients with R/R CLL were randomized, with groups receiving 400mg of venetoclax daily for 2 years and rituximab monthly for the first 6 months, or bendamustine and rituximab for 6 months, with a substudy of patients with progressive disease receiving VenR on the same schedule as the main study as a re-treatment or crossed over from the BR group.

“Overall, these data continue to support the use of fixed-duration VenR in R/R CLL and suggest that re-treatment with VenR is a viable option for pre-treated patients,” lead study author Arnon P. Kater, MD, of Amsterdam University Medical Centers, and colleagues wrote.

Patients assigned VenR saw 7-year progression-free survival (PFS) rates of 23.0% (95% CI, 16.1-29.9), and no patients treated with BR were progression-free at that point. The 7-year overall survival (OS) rates were 69.6% (95% CI, 62.8-76.5) for patients on VenR and 51.0% (95% CI, 43.3-58.7) for those treated with BR (HR = 0.53).

The median time to next treatment was 63.0 months vs 24.0 months for VenR and BR patients, respectively (HR = 0.30).

For VenR-treated patients who had undetectable minimal residual disease (uMRD) at the end of treatment (EOT) without progressive disease (PD) (n = 83/118; 70.3%), the mPFS from EOT was 52.5 months (95% CI, 44.5-61.5) vs 18.0 months (95% CI, 8.5-29.3; P < .0001) in patients who were MRD positive at the end of treatment (n = 35; 29.7%).

As of the 7-year update, 16.9% (n = 14) of patients with no PD or confirmed MRD conversion. The median time to conversion for the 75.9% (n = 63) of patients who had MRD conversion was 19.4 months (95% CI, 8.7-28.0). And of the patients who converted, 39 later had PD or died, with a median time of 28.3 months (95% CI, 23.2-35.0) from conversion to PD.

“This actually means, I think, a very clinically meaningful 4-year timeframe of treatment-free interval before this patient gets new treatment, so (this is) again showing not only the robustness of the treatment but also the very high predictive value of MRD in this combination,” Kater said during his presentation.

Twenty-five of the 34 patients who participated in the substudy were retreated with VenR, with the majority of them (92.0%) having at least 1 high-risk feature including IGHV-unmutated disease, genomic complexity, or del(17p) and/or TP53 mutations. Even with these high-risk features, 56.0% (14 out of 25) of patients reached uMRD at end of treatment in the main study.

There was a 72.0% best overall response rate (ORR) to re-treatment, and an mPFS of 23.3 months (95% CI, 15.6, 24.3). The median time between the last dose of venetoclax in the main study and ramp-up of the treatment in the substudy was 2.3 years (95% CI, 1.2-3.1). Eight patients (32.0%) reached uMRD at the end of the re-treatment phase of the combination treatment, but no patients maintained uMRD status at the end of re-treatment.

Researchers observed no new safety findings since the 5-year data cut.

“We think, therefore, that retreatment with VenR is a viable option of pretreated patients, and I think the longer the time is after VenR that you give a retreatment, I think probably the better the outcome will be,” Kater said. “And therefore, I think, these data continue to support the use of fixed duration treatment with venetoclax-rituximab in relapsed/refractory patients (and) also when patients have been treated with (a) target agent in the first line.”

Reference

Kater AP, Harrup R, Kipps TJ, et al. Final 7-Year Follow Up and Retreatment Substudy Analysis of MURANO: Venetoclax-Rituximab (VenR)-Treated Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL). Presented at the 2023 European Hematology Association Congress; Frankfurt Germany, June 8-11, 2023. Abstract S201.