Venetoclax/Rituximab Hits Over 80% 2-Year PFS Rate in CLL

John F. Seymour, MBBS, PhD

The combination of venetoclax and rituximab reduced the risk of disease progression or death by 83% versus bendamustine plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Findings from the phase III MURANO trial presented at the 2017 ASH Annual Meeting showed that the median progression-free survival (PFS) had not been reached with the venetoclax (Venclexta) plus rituximab (Rituxan) arm compared with 17.0 months in the bendamustine (Treanda) plus rituximab (BR) arm (investigator-assessed HR, 0.17; 95% CI, 0.11-0.25; P <.0001). The 2-year PFS rates were 84.9% versus 36.3%, respectively. A consistent PFS benefit with the venetoclax regimen was observed across all patient subgroups, including high- and low-risk groups.

The MURANO findings, “have the potential to establish venetoclax/rituximab as one of the standard options for the management of patients with relapsed or refractory CLL,” lead author John F. Seymour, MBBS, PhD, director of Cancer Medicine, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia, said when presenting the findings at ASH.

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 randomized 1:1 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 TP53 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).

Beyond the primary endpoint of PFS, secondary endpoints included best overall response, CR, duration of response, overall survival (OS), event-free survival, time to next CLL treatment, and minimal residual disease (MRD) status.

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).

Investigator-assessed overall response rate was 93.3% versus 67.7% with the venetoclax regimen versus BR, with compete response (CR)/CR with incomplete recovery of blood count rates of 26.8% versus 8.2%, respectively.

“The number of patients with disease progression was much smaller with venetoclax and rituximab,” noted Seymour.

The rate of MRD-negativity (<1 CLL cell in 10,000 leukocytes) at any time was also higher with venetoclax at 83.5% versus 23.1%. The median OS was not yet reached in either arm (HR, 0.48; 95% CI, 0.25-0.90; not statistically significant). Ongoing evaluation of OS continues.

Safety was evaluated in all 194 patients in the venetoclax arm and 188 patients in the BR arm. All patients in the venetoclax group and 98% of patients in the BR group experienced at least a grade 1 AE.

In the venetoclax arm, grade 3/4 AEs occurred in 82% of patients and serious AEs in 46% of patients. There were 10 patient deaths: pneumonia in 3 patients and sepsis, cardiac failure, myocardial infarction, sudden cardiac death, colorectal cancer, status epilepticus, and acute respiratory failure in 1 patient each.

Among patients receiving BR, grade 3/4 AEs occurred in 70% of patients and 43% of patients had serious AEs. There were 11 patient deaths: 2 cases each of sepsis and lung cancer, and 1 case each of Listeria sepsis, Scedosporium infection, lymphoma, hemorrhagic stroke, pulmonary embolism, AML, and sudden death.

Grade 3/4 AEs occurring at a higher incidence with venetoclax versus BR included neutropenia (58% vs 39%), tumor lysis syndrome (3% vs 1%), hyperglycemia (2% vs 0), and hypogammaglobulinemia (2% vs 0).

Patients receiving BR experienced higher grade 3/4 rates of anemia (14% vs 11%), thrombocytopenia (10% vs 6%), febrile neutropenia (10% vs 4%), pneumonia (8% vs 5%), infusion-related reaction (5% vs 2%), and hypotension (3% vs 0).

The FDA previously granted the venetoclax/rituximab combination a breakthrough therapy designation in January 2016. Additionally, the MURANO results are intended to support the conversion of the accelerated approval of single-agent venetoclax into a full approval for the treatment of patients with CLL who harbor a del(17p) and have received at least 1 prior therapy.

The breakthrough designation for venetoclax plus rituximab was based on data from the phase Ib M13-365 study. In the trial, the combination had an overall response rate of 86%, with deep and durable responses in patients with relapsed/refractory CLL.

Genentech (Roche) and AbbVie, the developers of venetoclax, reported in a press release that they plan to submit the MURANO findings to the FDA.

Seymour JF, Kipps TJ, MD2, Eichhorst BF, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/ refractory chronic lymphocytic leukemia - results from pre-planned interim analysis of the randomized phase 3 Murano Study. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract LBA-2.