Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, providing a new therapeutic option for this very poor prognosis population.

— Stephan Stilgenbauer, MD, and colleagues

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In a pivotal phase II study reported in The Lancet Oncology, Stephan Stilgenbauer, MD, of Ulm University, Germany, and colleagues found that the BCL2 inhibitor venetoclax (ABT-199) produced a high response rate in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with the 17p deletion (del [17p]).¹ The study supported the recent U.S. Food and Drug Administration approval of venetoclax (Venclexta) in this setting.

Study Details

In the single-arm study, 107 patients aged ≥ 18 years from 31 sites in the United States, Canada, UK, Germany, Poland, and Australia enrolled between May 2013 and June 2014 received oral venetoclax in a weekly ramp-up schedule of 20, 50, 100, 200, and 400 mg daily over 4 to 5 weeks followed by 400 mg daily until disease progression or treatment discontinuation for another reason. The primary endpoint was overall response on independent review committee assessment.

Patients had a median age of 67 years (57% ≥ 65 years); 65% were male; median number of prior treatments was 2 (range 1–4), including bendamustine in 50% (70% bendamustine [Treanda, Bendeka] refractory) and fludarabine in 73% (44% fludarabine refractory), with 58% overall being bendamustine or fludarabine refractory; 92% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 18% and 30% had Rai stage III and stage IV disease at entry; 39% had Binet stage C disease; 53% had bulky disease; neutropenia, anemia, and thrombocytopenia were disease-related complications in 22%, 21%, and 15%; 51% had an absolute lymphocyte count ≥ 25 × 10⁹/L; TP53 mutation, IGVH mutation, and 11q deletion were present in 72%, 19%, and 28%; and the median proportion of del(17p) cells was 50.3%.

Response Rate

At median follow-up of 12.1 months (interquartile range = 10.1–14.2 months), an overall response on independent review was achieved in 85 of 107 patients (79.4%, 95% confidence interval [CI] = 70.5%–86.6%). Responses consisted of complete remission or complete remission with incomplete recovery of blood cell counts in 8%, nodular partial remission in 3%, and partial remission in 69%. Median time to first response was 0.8 months. At the time of analysis, median duration of response, event-free survival, time to disease progression, progression-free survival, and overall survival had not been reached. Estimated 12-month progression-free survival was 72.0%, and estimated 12-month overall survival was 86.7%.

Exploratory post hoc analysis indicated that response rates were generally similar among subgroups (range, 70.8%–93.1%), including according to refractoriness to prior treatment, proportion of cells with del(17p), and presence of TP53 mutation. Among five patients who had progressed on ibrutinib (Imbruvica) or idelalisib (Zydelig), partial remission was observed in four. Among 87 patients with baseline lymphocytosis, 85 (98%) had a 50% reduction in absolute lymphocyte count at a median of 0.3 months. Among 45 patients with results available for peripheral blood minimal residual disease by flow cytometry, 18 had no detectable minimal residual disease; 10 of the 18 patients had bone marrow results available, with 6 having no minimal residual disease in bone marrow.

Toxicity

Grade 3 or 4 adverse events occurred in 65% of patients, with the most common being neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%). Serious adverse events occurred in 55%, with the most common being pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%). Neutropenia led to venetoclax interruption in 5% and dose reduction in 4%. Infection led to venetoclax interruption in 9% and dose reduction in 2%. Adverse events led to death within 30 days of the last dose of venetoclax in four patients, with none considered related to treatment.

The investigators concluded:

Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism of action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. ■

Disclosure: The study was funded by AbbVie and Genentech. For full disclosures of the study authors, visit www.thelancet.com

Reference

1. Stilgenbauer A, Eichhorst B, Schetelig J, et al: Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. Lancet Oncol 17:768-778, 2016.