Venetoclax Outperforms Standard Chemo-Immunotherapy in the Treatment of Relapsed/Refractory CLL

Treatment with the BCL2 inhibitor venetoclax and rituximab led to deeper and more durable responses than the combination of bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to results from the phase III MURANO trial.

“[The venetoclax combination] showed a significantly higher rate of progression-free survival (PFS) … than with a standard chemoimmunotherapy, with benefit observed in all subgroups analyzed,” John F. Seymour, MBBS, PhD, director of cancer medicine and the Department of Hematology at Peter MacCallum Cancer Centre in Melbourne, Australia, and co-authors reported. Their findings were published in The New England Journal of Medicine.

The international, randomized, open-label trial enrolled 389 patients from 109 sites in 20 countries between March 31, 2014, and September 23, 2015. Adult patients who received one to three prior therapies (including at least one chemotherapy-containing regimen) were eligible for the study. Those who previously received bendamustine could participate if the response after treatment lasted at least 24 months.

The median patient age was 65 years (range = 22-85 years), and a majority were men (73.8%). Patients had the following mutation status: del17p (n=92/342; 26.9%), TP53 (n=99/376; 26.3%), and IGHV (n=246/360; 68.3%).

Randomization was stratified according to del17p mutation status, responsiveness to previous therapy, and geographic region. All participants received intravenous (IV) rituximab 375 mg/m2 on day one of cycle one followed by 500 mg/m2 thereafter for six cycles, plus either:

  • IV bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle (n=195)
  • venetoclax administered via a 5-week ramp-up schedule, from 20 mg per day to 400 mg per day (n=194)

After completing the ramp-up period, patients continued venetoclax 400 mg as monotherapy for up to two years or until disease progression or unacceptable toxicity. Crossover between groups was not permitted.

By May 8, 2017 (data cutoff), 78 patients (40.2%) in the venetoclax cohort were still receiving therapy, and 68 patients (35.1%) had received the full two years of treatment. In the bendamustine group, 79 percent of patients (n=154) completed all six treatment cycles, while 34 patients did not. Exposure to rituximab was similar between the groups, the researchers noted.

After a median follow-up of 23.8 months (range = 0-37.4 months), the median PFS was not reached in the venetoclax cohort but was 17 months in the bendamustine cohort (p<0.001).

Rates of two-year, investigator-assessed PFS (primary endpoint) were higher in the venetoclax group: 84.9 percent versus 36.3 percent for the bendamustine arm (hazard ratio [HR] = 0.17; 95% CI 0.11-0.25; p<0.001). This finding was also observed in the subgroup of patients with or without del17p mutation. The rates of two-year PFS were:

  • 5% vs. 27.8% in the venetoclax and bendamustine groups, respectively, among patients with del17p mutation (HR=0.13; 95% CI 0.05-0.29)
  • 9% vs. 41.0%, respectively, in those without del17p mutation (HR=0.19; 95% CI 0.12-0.32)

Prespecified secondary efficacy measures, including the complete response rate [26.8% vs. 8.2%], the overall response rate [92.3% vs. 72.3%], and overall survival [91.9% vs. 86.6%], also favored venetoclax plus rituximab, the researchers reported (p values not provided). They added that, among the 366 patients (94.1%) who were evaluable for minimal residual disease (MRD) assessment, venetoclax was associated “with substantial rates of clearance of MRD on the basis of both peripheral-blood samples [62.4% vs. 13.3%; p value not provided] and bone marrow aspirate [27.3% vs. 1.5%; p value not provided].”

MRD status was predictive of subsequent PFS, the authors noted. The high rates of MRD with venetoclax “may indicate improved disease control over a longer term, even when therapy is discontinued,” they wrote (TABLE).

The time to subsequent treatment was numerically, but not significantly longer in the venetoclax group: At two years, 90.0 percent of patients in the venetoclax group and 52.1 percent in the bendamustine group had not received another CLL treatment (HR=0.19; 95% CI 0.12-0.31).

Nearly all patients (n=379; 99.2%) experienced at least one adverse event (AE), including every patient in the venetoclax cohort and 185 in the bendamustine cohort (98.4%). The most common AE in both cohorts was neutropenia (60.8% and 44.1%).

Grade 3/4 AEs appeared to be more common among venetoclax-treated patients (82% vs. 70.2%; p value not provided), which the authors noted was expected, “given the longer duration of treatment with venetoclax [median duration of exposure = 22.1 months; range = 0.1-27.9 months].” Neutropenia was the most common grade 3/4 AE and, again, this occurred more frequently in the venetoclax cohort (67.7% vs. 38.3%; p value not provided). However, grade 3/4 febrile neutropenia and infections or infestations were more common in the bendamustine cohort (9.6% vs. 3.6%; p value not provided).

Fatal AEs occurred in 5.2 percent of the venetoclax cohort and 5.9 percent of the bendamustine cohort, which included four fatal infections or infestations in each group. “No new safety events were observed in either treatment regimen,” the authors noted, and “the relatively small number of patients in the venetoclax-rituximab group [with] tumor lysis syndrome shows the effectiveness of the risk-mitigation procedures that were implemented during the trial and the generally safe delivery of the treatment.”

The study is limited by short duration of follow-up and divergence between investigator-assessed and independent review committee–assessed outcomes. Longer follow-up is needed to assess the durability of responses, the authors noted.

Genentech and AbbVie supported the study.

The corresponding authors report no financial conflicts.


Reference

Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107-20.

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