Venetoclax: Strong Showing in CLL

Stephan Stilgenbauer, MD

ASH 2015, ASH Highlights

Venetoclax, an oral, investigational, small molecule Bcl-2 inhibitor, achieved excellent and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (RR CLL). All patients in the trial harbored a 17p deletion, signaling poor prognosis.

In a pivotal phase 2 trial reported at the meeting, nearly 80% of patients with high-risk RR CLL achieved a response to venetoclax monotherapy; about 10% achieved a complete response (CR) or a partial response (PR), more than 20% of patients achieved minimal residual disease (MRD)-negative status, and responses were durable.

Three other new drugs have been approved in CLL: ibrutinib (BTK inhibitor), idelalisib (PI3K inhibitor), and obinutuzumab (anti-CD20—a more potent version of rituximab). Venetoclax attacks CLL by a different mechanism, inhibiting the Bcl-2 protein that prevents cell death, making it an attractive partner with other CLL drugs with a complementary mechanism of action.

Venetoclax has such strong antitumor activity that tumor lysis syndrome (TLS) emerged as a major concern in preliminary studies. This led the investigators to adjust the dosing schedule of venetoclax, initiating treatment at 20 mg/day and ramping up slowly over 4 weeks to a target dose of 400 mg. The new dosing schedule has not led to any clinical TLS, but there has been laboratory evidence of TLS in about 20% of patients in various trials.

“We saw deep responses and acceptable toxicity with venetoclax monotherapy in a relapsed/refractory population. Investigator-confirmed complete response was 7.5% and nodular partial response was 2.8%, with minimal disease negativity in greater than 20%,� said Stephan Stilgenbauer, MD, University of Ulm, Germany.

“In this study, venetoclax had a favorable risk-benefit profile. The risk of tumor lysis syndrome was effectively mitigated by our careful dosing strategy, and we saw no clinical tumor lysis syndrome,� Stilgenbauer said.

The pivotal study enrolled 107 patients with RR CLL with 17p deletions confirmed by a central laboratory. Median progression-free survival (PFS) with frontline chemotherapy is less than 12 months, he noted.

At baseline, median age was 67; 65% were male; median number of prior therapies was 2; and about 50% had previous bendamustine at relapse. About 42% were considered to be at high risk for TLS.

Median time on study was 12.1 months; 37 discontinued venetoclax due to disease progression, and 9 discontinued due to adverse events. There were 18 deaths, 14 due to progressive disease.

The primary end point of overall response rate as assessed by independent review committee was 79.4%, with a CR rate of 7.5% and a nodular PR rate of 2.8%. MRD was negative in peripheral blood in 18 of 45 patients.

Only 4 of 87 patients with baseline lymphocytosis did not normalize absolute lymphocyte count (ALC) on treatment. Median time to ALC normalization was 22 days.

Median time to first response was less than 1 month. Venetoclax achieves durable responses. Median time to response was not reached at the time of ASH.

The 12-month estimated rate of PFS is 72%, and 86.7% for overall survival (OS). Median OS has not yet been reached.

The most common adverse events were low-grade neutropenia, anemia, and thombocytopenia. Serious adverse events were reported in 55%. Adverse events of special interest were grade 3/4 neutropenia in 40%, infections in 72%, and TLS (lab measurements only) in 5 patients during the ramp-up dosing period. Only 2 patients required a dose interruption of 1 day.

Venetoclax is also being studied in combination with other drugs in CLL, including obinutuzumab, ri­tuximab, and bendamustine/rituximab. Phase 1b trials of these combinations were also reported at ASH. A phase 3 trial called MURANO is evaluating venetoclax in combination with rituximab versus rituximab plus bendamustine in a broader relapsed CLL population.

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