Final 7-Year Follow-Up Substudy of Using Venetoclax Combined with Rituximab for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

Authored by Dr. Brian Koffman

The Bottom Line:

In this final long-term analysis of the groundbreaking MURANO trial, progression-free survival (PFS) and overall survival (OS) benefits for venetoclax-rituximab (VenR) over bendamustine-rituximab (BR) were once again confirmed. Reaching undetectable measurable (minimal) residual disease or uMRD predicted prolonged PFS. And if patients relapsed, retreatment with VenR was a worthy option.

Who Performed the Research and Where Was it Presented:

Dr. Arnon Kater of the Amsterdam University Medical Center led the international group to present this research at the European Hematology Association (EHA) Annual Congress in Frankfurt in 2023.

Background:

The Phase 3 MURANO trial has previously reported superior PFS and OS with fixed-duration VenR versus BR in patients (pts) with relapsed refractory chronic lymphocytic leukemia (R/R CLL). At the 5-year update, the median PFS was 53.6 vs 17.0 months, and 5-year OS rates were 82.1% vs 62.2% (P<0.0001) in pts treated with VenR vs BR, respectively. This research presents the final 7-year update of that data.

Methods and Participants:

This is the final analysis of MURANO, with seven years median follow-up, focusing on updated PFS and OS, with MRD evaluation, in pts treated in the main study, as well as in the group of patients who had relapsed and were retreated with VenR in the substudy.

Methods:

Patients with R/R CLL were randomized to VenR (Venetoclax 400mg daily for two years + monthly R for the first six months) or BR (six months). In the substudy with data from 2018 and after, pts with progressive disease (PD) received VenR using the same schedule as the main study as either retreatment or as a crossover from BR.

Results:

• Data were collected until August 3^rd, 2022, the final cutoff.
• At that time, VenR-treated pts (n=194) had a median PFS of 54.7 months vs 17.0 months for 195 patients treated with BR.
• Seven-year PFS rates were 23.0% with VenR, while not one BR-treated patient remained progression-free at that time point.
• 7-year OS rates (95% CI) were 69.6% with VenR and 51.0% with BR.
• The median time to the next treatment with VenR was 63.0 months vs 24.0 months with BR.
• 37.1% of VenR-treated pts have not received subsequent anti-CLL treatment.
• Among VenR-treated pts who reached uMRD at the end of treatment (EOT) without progressive disease or PD (n=83/118; 70.3%), median PFS from EOT was 52.5 months vs 18.0 months in pts who were MRD+ at EOT (n=35; 29.7%).
• Fourteen (16.9%) pts had no PD nor confirmed MRD conversion at the 7-year update.
• In the 63 (75.9%) pts who had MRD conversion, the median time to conversion was 19.4 months.
• Among 63 pts who converted, 39 subsequently had PD or died; the median time from conversion to PD was 28.3 months.
• In the substudy group who needed subsequent therapy (n=34), 25 pts received VenR retreatment
  • 92.0% of whom had at least one of the following high-risk features:
    • IGHV-unmutated disease,
    • genomic complexity, or del(17p),
    • TP53 mutations.
  • Despite this, 14/25 (56.0%) achieved uMRD at EOT in the main study.
  • The best overall response rate (ORR) to retreatment was 72.0%, and the median PFS was 23.3 months.
  • The median (range) time between the last Ven dose in the main study and Ven ramp-up in the substudy was 2.3 (1.2–3.1) years.
  • Eight (32.0%) pts achieved uMRD at the retreatment end of combination treatment; however, no pts retained their uMRD status at the retreatment EOT.
• No new safety findings were observed since the 5-year data cut.

Conclusions:

In this final long-term analysis of the MURANO trial, PFS and OS benefits for VenR over BR were unsurprisingly sustained. There is no longer any ethical reason to do studies using BR when we have such strong data demonstrating the superiority of VenR.

Once again, we learn the deeper the remission, the better the prognosis. Reaching uMRD was associated with prolonged PFS. In those who were retreated with VenR, the overall response rate (ORR) was high, and uMRD was still attainable but not maintained in this high-risk population.

Overall, these data continue to support the use of fixed-duration VenR in R/R CLL and suggest that retreatment with VenR is a strong option for pre-treated pts.

Since the VenR combination was studied in the relapsed/ refractory (R/R) setting, that is the combination approved in the R/R setting. However, it is widely believed among CLL experts that combining venetoclax with obinutuzumab, which has proven to be a superior antibody to rituximab, would yield even better results and is often used “off-label.”

These results are most encouraging in difficult-to-treat patients, offering a powerful and durable therapy with a high likelihood of working a second time. Still, despite broad and deep response, less than 17% of patients in the primary group had no progress and maintained their uMRD status at the end of 7 years, and none in the retreated group.

We are still left looking for curative therapy. Still, venetoclax-based therapies have dramatically improved outcomes for CLL patients and are a convenient and smart treatment option for many in frontline and relapsed settings.

Links and Resources:

Watch my monologue on the EHA abstract:

To review all the details from this 2023 EHA abstract, click on 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).

Stay strong. We are all in this together.

Brian

Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.