Venetoclax monotherapy induces deep remissions in high-risk relapsed/refractory chronic lymphocytic leukemia with a 17p deletion

Results of a phase II study suggest that venetoclax, an oral, targeted drug that inhibits BCL-2, is a promising option for patients with chronic lymphocytic leukemia (CLL) harboring a 17p deletion. These patients have a particularly bad prognosis and very limited treatment options. In the presented study, including 107 patients, the overall response rate (ORR) with venetoclax was high at 79.4%. Interestingly, undetectable minimal residual disease (MRD) was observed in more than 20% of the responders and more than 10% of all patients achieved an independently assessed deep response. This is remarkable, as such depths of response have not yet been reported for this patients population.

CLL patients harboring a 17p deletion have a particularly poor prognosis and limited treatment options. In fact, the median progression-free survival (PFS) with frontline chemotherapy in these patients is shorter than 12 months. Venetoclax is an oral, targeted drug that inhibits BCL-2, a protein that regulates natural cell death. BCL-2 is overexpressed in CLL, leading to the accumulation of leukemic cells. In a previously reported phase I study with venetoclax, an ORR of 77% was reported in patients with relapsed or treatment-resistant CLL. Following these promising data, a pivotal phase II trial was conducted to assess the efficacy of venetoclax in CLL patients with a 17p deletion.

In total, 107 patients with relapsed/refractory CLL were treated with venetoclax once daily with a weekly dose ramp-up schedule. This ramp-up schedule was used to avoid tumor lysis syndrome in patients. Patients remained on a daily dose of 400 mg venetoclax until disease progression or discontinuation for another reason. The primary endpoint of the trial was ORR as assessed by an independent review committee. Efficacy was examined once patients had completed 36 weeks of venetoclax, experienced disease progression, or discontinued the trial. The secondary objectives of the trial included rates of complete (CR) and partial response (PR), time to first response, duration of response (DoR), PFS, overall survival (OS) and safety.

The reported ORR in the study was 79.4% (85/107). In 8 patients, a CR or a CR with incomplete bone marrow recovery (CRi) was observed, while 3 patients were shown to have a nodular PR. In 74 other patients a normal PR was reported. In total, 22 patients did not respond to the therapy. Of all responders, 84.7% maintained their response at 12 months. Of the 87 patients in the study who had baseline lymphocytosis, only 4 did not normalize to a level of white blood cells below 4x109/L. The median time to this normalization was short, at 22 days. The median time to the first response was 0.8 months, while the median time to a CR or CRi was 8.2 months. The MRD status was assessed in 45 patients and in 18 of them, MRD negativity was demonstrated. The overall median DoR, the median PFS, and the median OS were all not yet reached in the study. The 12-month PFS and OS rates were 72.0% and 86.7%, respectively.

The toxicity of venetoclax was acceptable in this extremely high-risk patient population. Grade 3/4 adverse events were reported in 76% of patients. This mainly consisted of neutropenia (40%), anemia (18%), or thrombocytopenia (15%). Of note, the rate of infections was low with venetoclax, with grade 3/4 upper respiratory tract infections as the most common high-grade infections in only 2% of the patients. Among the 11 deaths seen in the study, 7 were due to progressive disease, and 4 were related to adverse events.

In summary, venetoclax monotherapy achieved deep responses with acceptable toxicity in this very difficult-to-treat CLL patient population characterized by a 17p deletion. In over 10% of patients a CR, a CRi, or a nodal PR was reported and more than 20% of the analyzed patients was shown to be MRD-negative. As such, venetoclax may be an attractive component in novel treatment algorithms for del(17p) CLL.


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. Presented at ASH 2015; Abstract #LBA-6.

Speaker Stephan Stilgenbauer


Stephan Stilgenbauer, MD,
Associate Professor at the Department of Hematology, Oncology, Rheumatology and Infectious Diseases, University of Ulm, Germany


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