According to findings from the phase III MURANO trial recently published in the<em> New England Journal of Medicine, </em>the venetoclax (Venclexta) plus rituximab (Rituxan) regimen lowered the risk of disease progression or death by 83% in comparison with bendamustine (Treanda) plus rituximab (Rituxan) in patients with relapsed or refractory chronic lymphocytic leukemia<em>.</em>
John F. Seymour, MBBS, PhD
According to findings from the phase III MURANO trial recently published in theNew England Journal of Medicine,the combination of venetoclax (Venclexta) plus rituximab (Rituxan) lowered the risk of disease progression or death by 83% in comparison with bendamustine (Treanda) plus rituximab (Rituxan; BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
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) after a median follow-up period of 23.8 months. A PFS benefit for the venetoclax regimen found by an independent review committee was consistent with investigator findings (HR, 0.19; 95% CI, 0.13-0.28;P<.0001).
PFS benefit extended across all patients subgroups, including the high- and low-risk groups. Among patients with chromosome 17p deletion, the 2-year PFS rate was 81.5% in the venetoclax arm versus 27.8% with BR (HR, 0.13; 95% CI, 0.05-0.29). The 2-year PFS rate in patients without chromosome 17p deletion 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 favored the venetoclax group (84.9% vs 34.8%; HR, 0.17; 95% CI, 0.11-0.25). Overall survival (OS) rate favored the venetoclax arm at 24 months (91.9% vs 86.6%). However, the difference was not statistically significan, nor did either arm reach median OS (HR, 0.48; 95% CI, 0.25-0.90).
“[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," said lead author John F. Seymour, MBBS, PhD, director of Cancer Medicine, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia, who presented the MURANO results at the 2017 ASH Annual Meeting.
The MURANO trial was an open-label, international, multicenter phase III trial including 389 patients with relapsed/refractory CLL who had previously received between 1 and 3 lines of therapy with at least 1 chemotherapy regimen. These 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 to patients at 375 mg/m2on day 1, cycle 1, followed by 500 mg/m2on day 1 of cycles 2 through 6. Bendamustine regimen was administered at 70 mg/m2on days 1 and 2 of cycles 1 through 6.
The median age in the venetoclax arm was 64.5 (range 28-83), of which 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).
In the BR arm, the median age of patients 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 in this arm included alkylating agent (95%), purine analog (81%), anti-CD20 antibody (76%), and BCR inhibitor (3 patients).
The venetoclaxrituximab group did not reach median investigator-assessed PFS (114 events in 195 patients) compared to 17 months in the BR group (32 events of progression or death in 194 patients).
Investigator-assessed overall response rate (ORR) in the venetoclas regimen was 93.3% versus 67.7% in the BR group. The 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 higher with venetoclax at 83.5% versus 23.1%. Patients assigned to venetoclax had higher rates of clearance of minimal residual disease in the assessment of bone marrow aspirate (27.3% vs 1.5%).
At the May 8, 2017, data cutoff for primary analysis, 78 (40.2%) patients in the venetoclaxrituximab group were still receiving venetoclax monotherapy. In the BR group, 154 patients (79.0%) had completed all 6 cycles of the treatment. 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) during their treatments. The most common AE in both treatment groups was neutropenia, with 60.8% in the venetoclax arm and 44.1% of patients assigned to BR.
The venetoclax arm found grade 3/4 AEs to be more common, 82.0% versus 70.2%. The most common grade 3/4 AE was neutropenia 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, which was similar to the BR arm (n = 11; 5.9%).
Seymour JF, Kippes TJ, Eichhorst B, et al. Venetoclaxrituximab in relapsed or refractory chronic lymphocytic leukemia [published online March 22, 2018].N Engl J Med.2018; 378:1107-1120. doi: 10.1056/NEJMoa1713976.