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

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.

References

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