MURANO solidifies venetoclax-rituximab combo for relapsed/refractory CLL
Findings from the updated analysis of the phase III MURANO* trial solidify the role of fixed-dose venetoclax plus rituximab in a majority of patients with relapsed/refractory chronic lymphocytic leukaemia (CLL).
“After a median 36-months follow up and with all patients having completed therapy [for a] median 9.9 months, [progression-free survival (PFS)] remains significantly superior for venetoclax-rituximab compared with bendamustine-rituximab,” said study author Professor John Seymour from the Peter MacCallum Cancer Centre in Melbourne, Australia, at the recent meeting of the American Society of Hematology (ASH 2018).
A total of 389 patients with relapsed/refractory CLL were randomized to receive oral venetoclax (400 mg once/day for up to 2 years) plus intravenous rituximab (375 mg/m2 on day 1 of cycle 1 followed by 500 mg/m2 on day 1 of cycles 2–6 [28-day cycles]) or bendamustine (70 mg/m2 on days 1 and 2 of cycles 2–6) plus rituximab. A total of 130 patients completed the 2-year venetoclax-rituximab treatment without disease progression, while 154 completed the 6-cycle bendamustine-rituximab combination.
Superior PFS with venetoclax-rituximab
After a median follow-up period of 36 months with a median treatment exposure time of 24.4 and 5.5 months in the venetoclax-rituximab and bendamustine-rituximab arms, respectively, patients on venetoclax-rituximab demonstrated superior PFS compared with those on bendamustine-rituximab (3-year PFS rate, 71.4 percent vs 15.2 percent, hazard ratio [HR], 0.16, 95 percent confidence interval [CI], 0.12– 0.23). [ASH 2018, abstract 184]
These findings were similar to those of the primary analysis of the MURANO trial previously presented and published which showed a superior PFS with venetoclax-rituximab over bendamustine-rituximab after a median follow up of 23.8 months (2-year PFS rate, 84.9 percent vs 36.3 percent, median PFS, not reached vs 17.0 months, HR, 0.17; p<0.001). [N Engl J Med 2018;378:1107-1120]
The findings were consistent across subgroups including among patients with or without TP53 mutations, said Seymour.
Among the 130 patients who completed a median 9.9-month follow up off-treatment period, the estimated 12-month PFS was 87.4 percent. Following the venetoclax monotherapy period, most patients who received venetoclax did not experience disease progression, with 83 patients having undetectable minimal residual disease (MRD) status in peripheral blood at end of treatment (<10-4).
“The high rate of undetectable MRD observed with venetoclax-rituximab has been sustained to the timepoint of cessation of therapy and MRD status at that timepoint is a very strong predictor of durable PFS with our current follow up off-drug,” he said.
Results also alluded to a clinically meaningful improvement in overall survival (OS) with venetoclax-rituximab over bendamustine-rituximab which was maintained at 3 years (3-year OS rate, 87.9 percent vs 79.5 percent, HR, 0.50, 95 percent CI, 0.30–0.85).
“The OS benefit was seen despite the majority of the 91 patients in the bendamustine-rituximab arm who required further treatment receiving targeted agents,” said Seymour.
A greater proportion of patients who received bendamustine-rituximab required ≥1 subsequent treatments following disease progression compared with those who received venetoclax-rituximab (46.7 percent vs 13.9 percent).
A well-tolerated regimen
While neutropenia incidence was higher in venetoclax-rituximab compared with bendamustine-rituximab recipients (58.8 percent vs 39.9 percent), febrile neutropenia and pneumonia were rare and occurred at a lower rate in venetoclax-rituximab recipients (3.6 percent vs 9.6 percent [febrile neutropenia] and 5.2 percent vs 8.0 percent [pneumonia]). However, Seymour pointed out that the adverse event (AE) reporting period was longer in the venetoclax-rituximab than the bendamustine-rituximab arm. Grade 3–4 AEs were infrequent during the venetoclax monotherapy period (11.7, 2.9, and 1.8 percent for neutropenia, anaemia, and thrombocytopenia, respectively), with two episodes of pneumonia and none of febrile neutropenia. There was also no difference between venetoclax-rituximab and bendamustine-rituximab recipients with regard to Richter’s transformations (3.6 percent vs 3.2 percent).
“Overall, these data establish the feasibility and support the clinical utilization of fixed-duration venetoclax-rituximab for the majority of patients with relapsed/refractory CLL,” he said.
“Continuous exposure to single-agent venetoclax may lead to issues of resistance so my personal view is that aiming to achieve a time-limited therapy with combination targeted agents is desirable and a deep remission is necessary to allow cessation,” said Seymour. However, the right treatments and corresponding durations remain to be seen, he said.