Venetoclax/Rituximab Positive PFS Data Published in NEJM

John F. Seymour, MBBS, PhD

The regimen of venetoclax (Venclexta) plus rituximab (Rituxan) lowered the risk of disease progression or death by 83% versus bendamustine (Treanda) plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to findings from the phase III MURANO trial now published in the New England Journal of Medicine.

After a median follow-up period of 23.8 months, the progression-free survival (PFS) rate per investigator assessment was 84.9% for venetoclax/rituximab and 36.3% for BR (HR, 0.17; 95% CI, 0.11-0.25; P <.001). An independent review committee found a PFS benefit for the venetoclax regimen that was consistent with the investigator findings (HR, 0.19; 95% CI, 0.13-0.28; P <.0001).

The PFS benefit extended across patients subgroups, including high- and low-risk groups. The 2-year PFS rate among patients with chromosome 17p deletion was 81.5% in the venetoclax arm versus 27.8% with BR (HR, 0.13; 95% CI, 0.05-0.29). For patients without chromosome 17p deletion, the 2-year PFS rate was 85.9% versus 41.0% in favor of the venetoclax arm (HR, 0.19; 95% CI, 0.12-0.32).

Two-year event-free survival also favored the venetoclax group (84.9% vs 34.8%; HR, 0.17; 95% CI, 0.11-0.25). The rate of overall survival (OS) favored the venetoclax arm at 24 months (91.9% vs 86.6%). However, the difference was not statistically significant and neither arm reached median OS (HR, 0.48; 95% CI, 0.25-0.90).

Lead author John F. Seymour, MBBS, PhD, director of Cancer Medicine, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia, presented the MURANO results at the 2017 ASH Annual Meeting. He said at the time that the findings, “have the potential to establish venetoclax/rituximab as one of the standard options for the management of patients with relapsed or refractory CLL.”

The open-label, international, multicenter phase III MURANO trial included 389 patients with relapsed/refractory CLL who had previously received between 1 and 3 lines of therapy, including at least 1 chemotherapy regimen. Patients were randomly assigned to rituximab plus either venetoclax (n = 194) or bendamustine (n = 195).

Venetoclax was administered at 400 mg orally once daily from cycle 1, day 1 until progression, unacceptable toxicity, or a maximum of 2 years. Treatment was initiated with a 5-week ramp-up schedule with a dose beginning at 20 mg/day for 1 week and then gradually increased to the 400-mg dose. Rituximab was administered at 375 mg/m² on day 1, cycle 1, followed by 500 mg/m² on day 1 of cycles 2 through 6. The bendamustine regimen was 70 mg/m² on days 1 and 2 of cycles 1 through 6.

In the venetoclax arm, the median age was 64.5 (range 28-83), 27% (46/173) of patients had del(17p), 68% (123/180) of patients had unmutated IGHV, and 25% of patients harbored a TP53 mutation. One hundred eleven patients received 1 prior therapy, 57 patients had 2, 2 patients had 3, and 4 patients had more than 3. Prior treatments including alkylating agent (93%), purine analog (81%), anti-CD20 antibody (78%), and BCR inhibitor (5 patients).

The median age in the BR arm was 66.0 years (range, 22-85), 27% had del(17p), 68% (123/180) of patients had unmutated IGHV, and 28% of patients harbored a mutation. The number of prior therapies included 1 (n = 117), 2 (n = 43), 3 (n = 34), and more than 3 (n = 1). Prior therapies included alkylating agent (95%), purine analog (81%), anti-CD20 antibody (76%), and BCR inhibitor (3 patients).

Median investigator-assessed PFS was not reached in the venetoclax—rituximab group (114 events in 195 patients) compared with 17 months in the BR group (32 events of progression or death in 194 patients).

Investigator-assessed overall response rate (ORR) was 93.3% with the venetoclax regimen versus 67.7% for BR. Rate of compete response (CR)/CR with incomplete recovery of blood count was 26.8% versus 8.2% in favor of venetoclax.

The rate of minimal residual disease (MRD)-negativity (<1 CLL cell in 10,000 leukocytes) at any time was also higher with venetoclax at 83.5% versus 23.1%. In the assessment of bone marrow aspirate, patients assigned to venetoclax had higher rates of clearance of minimal residual disease (27.3% vs 1.5%).

At the May 8, 2017, data cutoff for the primary analysis, 78 (40.2%) patients in the venetoclax—rituximab group were still receiving venetoclax monotherapy. In the BR group, 154 patients (79.0%) had completed all 6 cycles of treatment. The median relative dose intensity was 97% with venetoclax and 100% with bendamustine.

All 194 patients in the venetoclax group and 185 (98.4%) patients in the BR group experienced at least 1 adverse event (AE). The most common any-grade AE in both treatment groups was neutropenia, 60.8% in the venetoclax arm and 44.1% of patients assigned to BR.

Grade 3/4 AEs were more common with venetoclax, 82.0% versus 70.2%. Neutropenia was the most common grade 3/4 AE with a higher incidence in the venetoclax arm (57.7% vs. 38.8%). However, incidences of grade 3/4 febrile neutropenia (3.6% vs 9.6%) and grade 3/4 infections or infestations (17.5% vs 21.8%) were lower in the experimental arm.

There were 10 (5.2%) patient deaths in the venetoclax arm, similar to the BR arm (n = 11; 5.9%).

Seymour JF, Kippes TJ, Eichhorst B, et al. Venetoclax—rituximab in relapsed or refractory chronic lymphocytic leukemia [published online March 22, 2018]. N Engl J Med. 2018; 378:1107-1120. doi: 10.1056/NEJMoa1713976.