February 2016, Vol. 5, No. 1

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Venetoclax: Strong Showing in CLL

Stephan Stilgenbauer, MD

ASH 2015, ASH Highlights

Stephan_Stilgenbauer98pxVenetoclax, 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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