Venetoclax/Rituximab Combo Approved in Europe for CLL

John F. Seymour, MBBS, PhD

The European Commission has approved venetoclax (Venclyxto, EU; Venetoclax, US) for use in combination with rituximab (Rituxan) for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) following at least 1 prior therapy.

The approval was based on findings from the phase III MURANO trial, results of which were published in the New England Journal of Medicine. After a median follow-up of 23.8 months, the progression-free survival (PFS) rate per investigator assessment was 84.9% for venetoclax plus rituximab and 36.3% for bendamustine plus rituximab (BR; HR, 0.17; 95% CI, 0.11-0.25; P <.0001). 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 median PFS was not reached with venetoclax plus rituximab compared with 18.1 months (95% CI, 15.8-22.3). The overall response rate was 92% versus 72%, respectively.

Two-year event-free survival also favored the venetoclax group (84.9% vs 34.8%; HR, 0.17; 95% CI, 0.11-0.25). Although the overall survival (OS) data were not yet mature, the rate of 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).

The venetoclax combination is now approved for this indication in all 28 member states of the EU, as well as Iceland, Liechtenstein and Norway.

"Chronic lymphocytic leukemia can relapse and become refractory to first-line treatment, and there is a need for better therapies to treat these patients who otherwise have limited options," John Seymour, MBBS, PhD, lead investigator of the MURANO trial and Director of Cancer Medicine at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia, said in a statement.

"The venetoclax plus rituximab combination provides these patients with an alternative treatment option that is superior to a type of chemoimmunotherapy and can achieve deep responses, as shown by MRD negativity rates in the peripheral blood and bone marrow, allowing for a fixed duration of treatment without the need for chemoimmunotherapy."

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).

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%).

The venetoclax/rituximab combination was approved in the United States for this indication in June 2018. In September 2018, the FDA added minimal residual disease data from the MURANO trial to the venetoclax label for this indication.

Prior to this combination approval, venetoclax was approved in the EU for single-agent use for the treatment of patients with CLL and 17p deletion or TP53 mutation who are not suitable for chemoimmunotherapy and are not suitable for or have failed on a BCR pathway inhibitor, as well as for patients who do not harbor those genomic alterations but have progressed after chemoimmunotherapy and a BCR inhibitor.

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.

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).