Long-term Follow-up Solidifies Role of Fixed-duration Venetoclax Plus Rituximab in Relapsed/Refractory CLL


Updated efficacy outcomes of the phase 3 MURANO trial demonstrated that fixed-duration venetoclax plus rituximab is an effective treatment approach for patients with relapsed/refractory chronic lymphocytic leukemia and did not compromise response to subsequent therapy or overall survival.

Rosemary Harrup, MBBS

Rosemary Harrup, MBBS

Updated efficacy outcomes of the phase 3 MURANO trial (NCT02005471) demonstrated that fixed-duration venetoclax (Venclexta) plus rituximab (Rituxan) is an effective treatment approach for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and did not compromise response to subsequent therapy or overall survival (OS).1

With a median follow-up of 59.2 months, investigators reported an approximate 80% reduction in the risk of progression or death (HR, 0.19; 95% CI, 0.15-0.26; P < .0001) and a 60% reduction in the risk of death (HR, 0.40; 95% CI, 0.26-0.62; P < .0001) with venetoclax/rituximab compared with bendamustine/rituximab.

Specifically, the median progression-free survival (PFS) was 53.6 months (95% CI, 48.4-57.0) in the investigative arm vs 17.0 months (95% CI, 15.5-21.7) in the control arm. The 5-year PFS rate was 37.8% (95% CI, 28.8%-46.8%) for venetoclax/rituximab; the rate was not estimable for the control arm.1

OS benefit was maintained for patients treated with venetoclax/rituximab vs bendamustine/rituximab with 5-year OS estimates of 82.1% (95% CI, 76.4%-87.8%) and 62.2% (95% CI, 54.8%-69.6%), respectively.

“At the 5-year update of MURANO, benefits in survival outcomes with venetoclax/rituximab were sustained,” wrote Rosemary Harrup, MBBS, director of Cancer Services at Royal Hobart Hospital in Hobart, Tasmania, Australia, in a poster of the data presented at the 2021 Pan Pacific Lymphoma Conference. “Fixed-duration venetoclax/rituximab is an effective approach [for] patients with relapsed/refractory CLL and results in improved OS over bendamustine/rituximab.”

Prior to venetoclax/rituximab therapy, bendamustine/rit

uximab served as the standard salvage therapy for patients with CLL who experienced progressive disease (PD). Investigators sought to establish a fixed-duration alternative for those who experience PD.2 The BCL-2 inhibitor venetoclax has demonstrated clinical efficacy for patients with relapsed/refractory CLL, including those with chromosome 17p deletions.

Based on 4-year follow-up data from the MURANO study, the National Comprehensive Cancer Network added the regimen as a category 1 recommendation to its guidelines for patients with relapsed/refractory CLL as a second or subsequent line of therapy.2,3

In the global, open-label, randomized MURANO trial, investigators compared the efficacy of fixed-duration venetoclax/rituximab with standard bendamustine/rituximab in 389 patients with relapsed/refractory CLL. Patients randomized to the experimental arm received a 5-week ramp-up schedule of venetoclax that increased the dose from 20 mg per day to 400 mg per day before day 1 of cycle 1. The doublet venetoclax/rituximab was then administered to 194 patients at 400 mg venetoclax daily plus standard-dose rituximab (375 mg/m2 intravenously [IV] on day 1 of cycle 1, and 500 mg/m2 IV day 1 of cycles 2 to 6 for the first 6 months. Following the end of the combination therapy (EOCT), venetoclax was continued for a maximum of 2 years from day 1, cycle 1.1,4

The doublet bendamustine/rituximab was given to 195 patients at 70 mg/m2 bendamustine and standard-dose rituximab for 6 months. Following progressive disease, patients were allowed to crossover or be retreated with venetoclax/rituximab.

The primary end points of the trial were PFS and OS. The secondary end point was overall response rate (ORR). Eligible patients must have been treated with 1 to 3 prior lines of therapy including at least 1 standard chemotherapy-containing regimen.1,4

Investigators explored whether undetectable minimal residual disease (uMRD) could serve as a surrogate for long-term improved outcomes. Rates of clearance were determined using a threshold of less than 1 tumor cell per 10,000 white cells assessed via polymerase-chain reaction assay.1,4

A trend in improved OS outcome was observed among venetoclax-rituximab-treated patients who reached end of treatment (EOT) without PD and with uMRD (n = 83/118) compared with those with MRD (n = 35/118). Two- and 3-year post-EOT survival estimates were reported at 98.8% (95% CI, 96.4%-100%) vs 88.6% (95% CI, 78.0%-99.1%) and 95.3% (95% CI, 90.0%-100.0%) vs 85.0% (95% CI, 72.8%-97.2%), respectively. The HR for OS since EOT for those with uMRD vs those with MRD positivity was 3.16 (95% CI, 0.70-14.22; P = .1192).1

Harrup and colleagues noted that longer follow-up is required to establish uMRD as a predictive marker.

Long-term investigator-assessed PFS for patients treated with venetoclax/rituximab were also stratified by MRD level. Specifically, investigators reported the 2-year and 3-year PFS rates for those with uMRD (n = 83), low MRD (n = 23), and high MRD (n =12). Patients with low MRD performed better in the EOT setting compared with those who had high MRD at both time points (HR, 0.31; 95% CI, 0.10-0.99; P = .0410).

The greatest benefit was observed when comparing those with uMRD to those with high MRD (HR, 0.02; 95% CI, <0.01-0.18; P < .0001). The 2-year PFS rates for those with uMRD, low MRD, and high MRD were 85.4% (95% CI, 77.4%-93.4%), 52.2% (95% CI, 31.8%-72.6%), and 8.3% 95% CI, 0.0%-24.0%), respectively. Three-year PFS rates were 61.3% (95% CI, 47.3%-75.2%), 40.7% (95% CI, 19.2%-62.6%), and not estimable, respectively.

Compared with bendamustine/rituximab, fewer patients treated with venetoclax/rituximab-treated who experienced PD received subsequent anti-CLL therapy. Of the patients who experienced PD following initial treatment in MURANO, 77% (n = 67/87) of those who received venetoclax/rituximab and 83.1% (n = 123/148) of those who received bendamustine/rituximab received subsequent anti-CLL therapy.

Subsequent anti-CLL therapies for those with PD included venetoclax (47.8% and 12.2% following venetoclax/rituximab and bendamustine/rituximab, respectively), Bruton tyrosine kinase (BTK) inhibitors (26.9% and 58.5%), chemoimmunotherapy (22.4% and 19.5%) or treatment with another novel agent (3.0% and 9.8%).

Harrup et al reported ORRs to subsequent BTK inhibitor–based therapy or venetoclax-based regimens were high in patients with PD across both treatment arms. Patients who received venetoclax/rituximab and went on to receive a BTK inhibitor (n = 14), the ORR was 100%, comprising a 92.9% partial response (PR) and 7.1% complete response (CR) with a median duration of response of 29.1 months (range, 5.6-59.2). For those in the bendamustine/rituximab arm (n = 56), the ORR was 83.9% with a 67.9% PR rate, 16.1% CR rate, and a median DOR of 26.6 months (range, 0-50.4). In total, 5.4% of patients in this group experienced PD.

For those treated with venetoclax-based therapies, 32 patients were retreated in the venetoclax/rituximab arm (21 within the retreatment arm of the MURANO sub-study and 11 outside of the sub-study) and 18 were evaluable for response. The ORR for these patients was 72.2% (PR, 66.7%; CR, 5.6%) with 11.1% of retreated patients experiencing PD or no response, respectively. For the 10 patients in the bendamustine/rituximab arm (n = 10), the ORR was 80.0% (PR, 50.0%; CR, 30.0%) with 10% of patients experiencing PD.

Time to next therapy and time to second PFS (PFS2) event were longer following venetoclax/rituximab treatment vs bendamustine/rituximab. The median time to next therapy from study entry was 57.8 months (95% CI, 55.1-not estimable) vs 23.9 months (95% CI, 20.7-29.5), respectively (HR, 0.26; 95% CI, 0.20-0.35; P < .0001). The median time to PFS2 event was not estimable for those in the venetoclax/rituximab arm vs 46.9 months (95% CI, 40.8%-48.4%) in the bendamustine/rituximab arm (HR, 0.19; 95% CI, 0.12-0.29; P < .001).

No new safety signals were identified during the 3 years post-EOT.


  1. Harrup R, Kater AP, Kipps TJ, et al. 5-year update of the MUANO trial in relapsed or refractory chronic lymphocytic leukemia following fixed-duration venetoclax-rituximab therapy. Presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021; Big Island, HI.
  2. Kater AP, Qu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi:10.1200/JCO.20.00948
  3. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 2.2021. Accessed August 17, 2021. nccn.org/professionals/physician_gls/pdf/cll.pdf
  4. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976
Related Videos
Jean L. Koff, MD, MS
David L. Porter, MD, director, Cell Therapy and Transplant, Jodi Fisher Horowitz Professor in Leukemia Care Excellence, Penn Medicine
Changchun Deng, MD, PhD
Changchun Deng, MD, PhD, associate professor, hematology/oncology, University Hospitals Seidman Cancer Center; member, Immune Oncology Program, Case Comprehensive Cancer Center
Bhagirathbhai Dholaria, MBBS, associate professor, medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center
Jennifer Brown, MD, PhD
Saad J. Kenderian, MB, CHB
Eduardo Sotomayor, MD
Saad J. Kenderian, MB, CHB
Jennifer Brown, MD, PhD