Venetoclax Improved Response in High-Risk Relapsed, Refractory CLL

The oral BCL-2 inhibitor venetoclax elicited a high rate of response from patients with high-risk relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion, according to results of a phase II study (abstract LBA-6) presented at the 57th Annual American Society of Hematology (ASH) Meeting and Exposition, held December 5–8 in Orlando, Florida.

According to Stephan Stilgenbauer, MD, PhD, of the University of Ulm, Ulm, Germany, who presented the results during a press conference, venetoclax targets a key biological phenomenon of CLL, BCL2, which is highly expressed in CLL cells. A prior phase I study of venetoclax showed an overall response rate of 79% in patients with relapsed/refractory disease.

In this phase II study, Stilgenbauer and colleague enrolled 107 patients with relapsed/refractory del (17p) CLL. Patients with 17p deletions have a particularly poor prognosis and limited treatment options.

Patients were assigned to venetoclax once daily with the weekly dose increasing from 20 mg to 400 mg during a 5-week period. Patients were continued on the 400-mg dose until disease progression or drug discontinuation. In addition, all patients underwent tumor lysis syndrome prophylaxis.

The primary objective of the study was overall response rate, which was determined by both independent review committee and the investigators.

The efficacy analyses took place at 36 weeks of treatment. The median time on study was 12.1 months.

The overall response rate as assessed by independent review was 79.4% (95% confidence interval [CI], 70.5%–86.6%). Among the responders, 7.5% achieved complete response and 2.8% achieved nodular partial response. In addition, among the 69.2% of patients who had a partial response and the 20.6% with no response, 17 patients (15.9%) had no morphologic evidence of disease in bone marrow. Of all responders, 84.7% maintained their response at 12 months.

Minimal residual disease was assessed in 45 patients. The researchers noted that 18 patients-or about one in five of the responders-had no detectable minimal residual disease in the peripheral blood and 6 patients had none in the bone marrow.

The researchers also analyzed the change in absolute lymphocyte count from baseline to best response. They found that 4 of the 87 patients with baseline lymphocytosis did not normalize their count to less than 4 x 10⁹. The median time to normalization was 22 days.

According to Stilgenbauer, patients had a very rapid time to response. The median time to first response was 0.8 months, and the median time to complete response was 8.2 months.

The safety analysis showed the grade 3/4 neutropenia was observed in 40% of patients. Stilgenbauer noted that this rate was not surprising in patients who had undergone multiple lines of prior treatment. Eleven deaths occurred; seven were due to progressive disease and four due to adverse events.

Based on the results of this analysis, Stilgenbauer said that venetoclax is an attractive component to novel combinations or sequencing with other agents in the treatment of patients with CLL with 17p deletions.