Long-Term Data Support Venetoclax Plus Rituximab in Relapsed/Refractory CLL

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Venetoclax (Venclexta) in combination with rituximab (Rituxan) demonstrated long-term survival benefits vs bendamustine plus rituximab (BR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from the final analysis of the phase 3 MURANO trial (NCT02005471) published in Blood.1

At a median follow-up of 7 years, the median progression-free survival (PFS) among patients who received venetoclax plus rituximab (n = 194) was 54.7 months (95% CI, 52.3-59.9) compared with 17.0 months (95% CI, 15.5-21.7) in the BR arm (n = 195; HR, 0.23; 95% CI, 0.18-0.29; P < .0001). The 7-year PFS rate in the investigational arm was 23.0% (95% CI, 16.1%-29.9%); all patients in the control arm had experienced disease progression at this time point. The median OS in the investigational and control arms was not reached (NR) compared with 87.8 months (95% CI, 70.1-NR]), respectively (HR, 0.53; 95% CI, 0.37-0.74; P = .0002). The respective 7-year OS rates were 69.6% (95% CI, 62.8%-76.5%) and 51.0% (95% CI, 43.3%-58.7%).

“This final long-term analysis of MURANO continues to demonstrate clinically meaningful results for fixed-duration venetoclax and rituximab in patients with relapsed/refractory CLL,” the study authors wrote. “Based on [findings from] the substudy, retreatment with venetoclax and rituximab is a viable option after initial venetoclax and rituximab treatment; its implementation in routine clinical practice deserves further investigation.”

Prior data from MURANO supported the June 2018 FDA approval of venetoclax for the treatment of patients with chronic CLL or small lymphocytic lymphoma, with or without a 17p deletion, who received a minimum of 1 previous therapy.2

MURANO Study Design and Baseline Characteristics

MURANO was a global, open-label study that enrolled adult patients with relapsed/refractory CLL who received 1 to 3 prior lines of therapy.3 Patients were also required to have an ECOG performance status of 0 or 1, as well as adequate bone marrow, renal, and hepatic function. Additionally, patients were permitted to have received prior bendamustine if they experienced a duration of response (DOR) of at least 24 months.

Patients were randomly assigned 1:1 to receive venetoclax plus rituximab or BR. In the investigational arm, venetoclax was administered at a dose of 400 mg daily for 2 years after ramp-up dosing, and rituximab was given at a dose of 375 mg/m2 on day 1 of cycle 1, followed by 500 mg/m2 on day 1 of cycles 2 through 6 via 28-day cycles. Patients in the control arm received 70 mg/m2 of bendamustine on days 1 and 2 of each cycle for 6 cycles plus rituximab at the same dosing schedule as the investigational arm.

The primary end point was investigator-assessed PFS. Secondary end points included independent review committee–assessed PFS, overall response rate (ORR), OS, DOR, and event-free survival (EFS), and safety.

At baseline, the mean patient ages in the investigational and control arms were 63.9 years (SD, 10.5) and 64.4 years (SD, 9.6), respectively.1 Most patients in both arms were male (70.1% vs 77.4%), received 1 prior anticancer therapy (57.2% vs 60.0%), did not have TP53-mutated disease (74.2% vs 67.7%), and did not have IGHV-mutated disease (68.3% vs 68.3%).

Substudy Findings and Safety Data

Additional findings from the final analysis of MURANO demonstrated that the median EFS in the investigational and control arms was 53.7 months (95% CI, 48.5-59.3) vs 16.4 months (95% CI, 14.2-21.0), respectively (HR, 0.22; 95% CI, 0.17-0.29; P < .0001). The median DOR was 53.6 months (95% CI, 49.1-57.0) in the investigational arm vs 19.1 months (95% CI, 16.1-23.6) in the control arm (HR, 0.23; 95% CI, 0.17-0.31).

Data from a substudy of patients who crossed over to the venetoclax plus rituximab arm (n = 9) or were retreated with the venetoclax/rituximab regimen (n = 25) revealed that the median PFS values were 26.7 months (95% CI, 21.3-NR) and 23.3 months (95% CI, 15.6-24.3), respectively. The median OS was NR in both groups. The best ORR in the retreatment group was 72.0%, including 6 patients who achieved a complete response (CR). The best ORR in the crossover group was 88.9%, including 2 patients who achieved a CR. The median DORs were 15.5 months (95% CI, 11.5-NR) and 22.5 months (95% CI, 12.7-not estimable), respectively.

The safety profiles of the investigational and control regimens were consistent with primary findings from MURANO. Any-grade adverse effects (AEs) occurred at rates of 100.0% and 98.4%, respectively. Patients in both arms experienced AEs with a fatal outcome (9.3% vs 9.0%), serious AEs (52.1% vs 44.7%), treatment-related serious AEs (22.7% vs 27.1%), and grade 3 or 4 AEs (77.3% vs 64.4%). Patients died at respective rates of 30.9% and 44.7%.

“No new safety findings were observed. Overall, these [data from the] final MURANO analyses support consideration of fixed-duration venetoclax and rituximab therapy for patients with relapsed/refractory CLL,” the study authors noted.

References

1. Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood. 2025;145(23):2733-2745. doi:10.1182/blood.2024025525
2. FDA approves venetoclax for CLL or SLL, with or without 17 p deletion, after one prior therapy. FDA. June 8, 2018. Accessed June 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-or-sll-or-without-17-p-deletion-after-one-prior-therapy
3. 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