1. Fuerst, Mark L.

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ATLANTA-A combination of venetoclax plus rituximab (VR) is superior to standard chemotherapy with bendamustine plus rituximab (BR) in patients with relapsed/refractory chronic lymphocytic leukemia, according to a new study.

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In a phase III trial presented at the 2017 American Society of Hematology Annual Meeting, treatment with the targeted cancer drug venetoclax in combination with rituximab more than doubled the likelihood that patients with chronic lymphocytic leukemia (CLL) would survive for 2 years without cancer progression compared to treatment with the standard chemo-immunotherapy drug bendamustine with rituximab (Abstract LBA-2).


"This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach," said lead author John Seymour, MBBS, PhD, Director of the Haematology Department at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.


"It suggests that venetoclax should replace chemotherapy for relapsed/refractory CLL and is suggestive that the combination with rituximab is the preferred manner to use the drug. There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this setting.


"Venetoclax plus rituximab should be considered as a standard therapeutic option in patients with relapsed/refractory CLL," he added.


Overview of Venetoclax

Venetoclax is designed to hasten the death of leukemia cells by binding to and blocking the activity of the BCL-2 protein. Bendamustine works by interfering with cancer cells' DNA. Rituximab is a monoclonal antibody designed to help the body's immune system recognize and attack leukemia cells, Seymour explained.


Venetoclax is approved for use against CLL in the U.S. and several other countries, but approvals are limited to small subgroups of patients, including those with a specific genetic abnormality. The new trial, carried out at 109 sites globally, sought to assess the safety and efficacy of venetoclax in a broad patient population.


Venetoclax is an orally administered, highly selective, potent BCL-2 inhibitor that induces high overall response rate (ORR) when given as monotherapy to patients with relapsed/refractory CLL, including patients with poor prognostic factors, such as del(17p), Seymour noted. Venetoclax is also well-tolerated when combined with rituximab and achieves improved complete remission rates and minimal residual disease (MRD)-negativity.


MURANO Trial Details

MURANO is an open-label, randomized, phase III trial that included relapsed/refractory CLL patients requiring treatment who had 1-3 prior lines of therapy, including one or more chemotherapy-containing regimens and ECOG performance status of 0 or 1. Seymour presented an interim analysis of 389 patients (VR 194 patients, median age 64.5; BR 195 patients, median age 66 years). About one-quarter of patients in both arms had del(17p).


In the VR arm, a 4-week or 5-week graduated dose ramp-up of venetoclax from 20-400 mg daily was used to mitigate the risk of potential tumor lysis syndrome (TLS). Beginning at week 6, rituximab was then given monthly for six 28-day cycles intravenously 375 mg/m2 first dose, then 500 mg/m2 in combination with venetoclax daily. Patients continued with venetoclax 400 mg for a maximum of 2 years or until disease progression.


In the BR arm, patients were given bendamustine intravenously 70 mg/m2 on days 1 and 2 of each of six 28-day cycles in combination with rituximab using the same rituximab dosing schedule.


After a median follow-up of 2 years, there was a "profound, clear difference in PFS," he said. Patients achieved significantly prolonged median PFS, the primary endpoint, with VR (median PFS, not reached) as compared with BR (median PFS, 17.0 months). The 24-month PFS estimates were 84.9 percent in the VR group versus 36.3 percent in the BR group.


Venetoclax also outperformed bendamustine for the trial's secondary endpoints, which included overall survival and markers of cancer remission. The 2-year overall survival was notably higher with VR (91.9%) than with BR (86.6%). Higher peripheral blood MRD-negativity rates attained at any time were significantly higher with VR (83.5%) than with BR (23.1 %t), and MRD negativity was more durable in the VR arm.


These results suggest venetoclax could be discontinued after 2 years with a low risk of recurrence in those patients with a deep remission, he said. So far, 65 patients who have ceased therapy after 2 years are progression-free, and 12 of these patients have 3 or more months of follow-up.


The safety profiles were consistent with the regimens, with no new signals. Grade 3/4 neutropenia was higher in the VR arm, but there was no increase in febrile neutropenia or grade 3/4 infection. TLS was reported in 3.1 percent of VR patients and 1.1 percent of BR patients. While venetoclax was associated with a greater risk of abnormally low white blood cell counts, there was no increase in severe infections or deaths related to this side effect, Seymour noted.


Confirmed Richter transformation occurred in six VR patients and five BR patients. Adverse events leading to death were seen in 10 (5.2%) VR patients and in 11 (5.9%) BR patients.


"Venetoclax plus rituximab was superior to bendamustine plus rituximab in prolonging PFS in adults with relapsed/refractory CLL," Seymour stated. "The effects are consistent across subgroups, regardless of del(17p) status, with superior ORR and rate of peripheral blood MRD-negativity that was maintained over time and clinically meaningful improvement in overall survival. Safety was consistent with the known safety profile in patients with relapsed/refractory CLL.


"This enhanced disease control was achieved in a multinational setting with an acceptable safety profile, without significant TLS, demonstrating that treatment with VR resulted in outcomes superior to that of BR for patients with relapsed/refractory CLL."


Further follow-up is required to evaluate duration of benefit after venetoclax cessation.


Mark L. Fuerst is a contributing writer.