ORLANDO, FLIn “ultra-high risk” patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring 17p deletion, treatment with venetoclax monotherapy resulted in a high overall response rate and sustained remissions, a pivotal international phase 2 study reported at the 57th American Society of Hematology (ASH) Annual Meeting.1

“Venetoclax may provide an attractive treatment option for 17p deletion CLL as monotherapy or in the future as a component of novel combination strategies,” said Stephan Stilgenbauer, MD, PhD, of University of Ulm in Germany.

Previously, a first-in-human study showed an overall response rate of 79% for venetoclax in patients with relapsed/refractory CLL, including del(17p), considered to be a population with a very poor prognosis.

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In this study, venetoclax, an “orally bioavailable, selective BCL-2 inhibitor that induces apoptosis in CLL cells independent of p53,” was evaluated as monotherapy in 107 patients. Venetoclax was administered once daily, with a weekly dose ramp-up schedule of 20 mg (test), 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks, with risk-based prophylaxis to mitigate tumor lysis syndrome.

Median age was 67 years (range, 37-85) and 65% were male. The majority of patients (72.9%) had received prior fludarabine and bendamustine, with half refractory to therapy; the median number of prior regimens was 2 (range, 1-10). Only 1 patient did not have a 17p deletion, and investigators reported 60 of 83 patients (72.3%) with available data had a TP53 mutation.

As of April 30, 2015, median time on study was 12.1 months (range, 0.03-21.5).

The primary end point, independent review committee-assessed overall response rate, was 79.4% (95% CI: 70.5-86.6). Deep responses included 8 (7.5%) complete remission (CR)/CR with incomplete platelet recovery (CRi) and 3 (2.8%), near partial remission (nPR).

A total of 74 patients achieved PR (69.2%, excluding nPR) and 22 did not respond to treatment (20.6%). Of 48 patients, 25 had no CLL in the bone marrow,  Dr. Stilgenbauer reported.

A total of 45 patients were assessed for minimal residual disease (MRD) and 18 (17% of entire cohort, 21% of those who responded to treatment) had no detectable MRD in peripheral blood.

Median time-to-first response was 0.8 months (range, 0.1-8.1), and median time to CR/CRi was 8.2 months (range, 3.0-16.3). Overall median duration of response, progression-free survival, and overall survival were not reached.

The actuarial 12-month rate for progression-free survival was 72.0% and the overall survival rate was 86.7%. For duration of response, the 12-month rate was 84.7% among the 85 responders; 100% for the 11 patients defined as being deep responders (CR, CRi, nPR), 82.6% for the 74 patients in partial remission, and 94.4% for the 18 patients who were MRD-negative.

Treatment-emergent adverse events (all grades) included neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), and fatigue (22%); 22.4% of patients had baseline neutropenia. Serious adverse events occurred in 55% of patients; the most common was pyrexia in 7%, autoimmune hemolytic anemia in 7%, pneumonia in 6%, and febrile neutropenia in 5%.

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The incidence of neutropenia and infection are similar to that observed with other frontline chemoimmunotherapy regimens, he said.

Laboratory tumor lysis syndrome was reported in 5 patients during the ramp-up period; “none had clinical consequences, and all were manageable with electrolyte management and 1-day dose interruption” in 2 patients, Dr Stilgenbauer reported.


  1. Stilgenbauer S, Eichhorst BF, Schetelig J, et al. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase 2 study. Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 8, 2015; Orlando, FL.